KR20080048551A - Method for 1h-imidazo[4,5-c]pyridines and analogs thereof - Google Patents

Abstract

Methods and intermediates for preparing compounds of the Formulas: (I and X) are disclosed. The methods include a method providing a compound of the Formula: (IV) and converting a compound of Formula IV to a compound of Formula I, a method providing a compound of the Formula: (VIII) and converting a compound of Formula VIII to a compound of Formula I, and a method providing a compound of the Formula: (XI) and converting a compound of Formula XI to a compound of Formula I.

Description

Preparation of 1H-imidazo [4,5-c] pyridine and analogues thereof {METHOD FOR 1H-IMIDAZO [4,5-c] PYRIDINES AND ANALOGS THEREOF}

Cross Reference to Related Application

This application claims priority to US Provisional Application No. 60/720171, filed September 23, 2005, and US Provisional Application No. 60/743505, filed March 16, 2006, both of which are incorporated herein by reference. Insist.

Certain compounds have been found to be useful as immune response modulators (IRMs) useful in the treatment of various diseases. However, with the introduction of cytokine biosynthesis or other mechanisms, there has been a continuing interest and desire for compounds that have the ability to modulate immune responses. Thus, there is a need for methods and intermediates for the preparation of such compounds.

<Overview of invention>

In accordance with the present invention, certain 1H-imidazo [4,5-c] pyridine and analogs thereof, or pharmaceutically acceptable salts thereof, provide a compound of Formula IV, wherein the compound of Formula IV is a compound of Formula R ₁ NH ₂ It has been found that it can be prepared by a method comprising reacting with an amine to provide 1H-imidazo [4,5-c] pyridine or an analog thereof, or a pharmaceutically acceptable salt thereof.

Wherein E, L, R ₁ , R ₂ , R _A , and R _B are as defined below.

In other embodiments, certain 1H-imidazo [4,5-c] pyridine and analogs thereof, or pharmaceutically acceptable salts thereof, provide a compound of Formula VIII, wherein the compound of Formula VIII is a compound of Formula R ₁ NH ₂ By reacting with an amine to provide 1H-imidazo [4,5-c] pyridine or an analog thereof, or a pharmaceutically acceptable salt thereof.

<Formula I>

Wherein E, L, R ₁ , R ₂ , R ₁₁ , R ₁₂ , R _A , and R _B are as defined below.

In other embodiments, certain 1H-imidazo [4,5-c] pyridine and analogs thereof, or pharmaceutically acceptable salts thereof, provide a compound of Formula XI and the 1H-imidazo [4,5 of Formula I -c] pyridine or an analog thereof, or a pharmaceutically acceptable salt thereof.

<Formula I>

Wherein E, L, R ₁ , R ₂ , R _A , and R _B are as defined below.

Compounds of formula (I) and salts are useful for preparing the immune response modulating compounds of formula (X) or pharmaceutically acceptable salts thereof.

Wherein R ₁ , R ₂ , R _A , and R _B are as defined below.

Compounds and salts of formula (X), when administered to an animal, induce or inhibit cytokine biosynthesis (e.g., induce or inhibit the biosynthesis of at least one cytokine), and in their ability to otherwise modulate immune responses It is known to be useful as a modulator of immune response. This makes these compounds and salts useful for the treatment of viral diseases and tumors that are sensitive to such changes in various symptoms, such as immune responses.

In one embodiment, providing a compound of Formula IV and reacting the compound of Formula IV with an amine of Formula R ₁ NH ₂ , wherein 1H-imidazo [4,5-c] pyridine or an analog thereof, or a pharmaceutical thereof Provides a phase-acceptable salt, and converts E to an amino group in the compound of Formula I to give a compound of Formula X (1H-imidazo [4,5-c] pyridin-4-amine or an analog thereof), or a pharmaceutically acceptable It provides a method comprising providing a salt.

<Formula IV>

<Formula I>

<Formula X>

Wherein E, L, R ₁ , R ₂ , R _A , and R _B are as defined below.

In another aspect, the present invention provides intermediates useful for the preparation of immune response modulators. In one embodiment, a compound of Formula (XI) is provided.

<Formula XI>

Wherein E, L, R ₁ , R _A , and R _B are as defined below.

As used herein, "one", "one", "that", "at least one", and "one or more" are used interchangeably.

The term "comprises" and variations thereof do not have a limiting meaning where these terms appear in the specification and claims.

The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The following description more particularly describes exemplary embodiments. In some cases of the entire specification, enumeration of the embodiments provides guidance that the embodiments can be used in various combinations. In each case, the list mentioned merely represents a representative group and should not be construed as a comprehensive list.

The present invention provides certain 1H-imidazo of Formula I, useful for preparing compounds of Formula X (1H-imidazo [4,5-c] pyridin-4-amine or analogs thereof), or pharmaceutically acceptable salts thereof. Provided are methods and intermediates for preparing [4,5-c] pyridine and analogs thereof, or pharmaceutically acceptable salts thereof.

<Formula I>

<Formula X>

Wherein E, R ₁ , R ₂ , R _A , and R _B are as defined below.

In one embodiment, providing a compound of Formula IV and reacting the compound of Formula IV with an amine of Formula R ₁ NH ₂ , wherein 1H-imidazo [4,5-c] pyridine or an analog thereof, or a pharmaceutical thereof Process (i) is provided comprising providing a phase acceptable salt.

<Formula IV>

<Formula I>

In the formula,

E is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -OS (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is alkyl Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by halo, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl Or; or

E combines with adjacent pyridine nitrogen atoms of Formulas I and IV to form a ring with fused tetrazole in Formulas I-1 and IV-1;

[Formula I-1]

[Formula IV-1]

L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -OS (O) ₂ -R ', wherein R' is alkyl, halo, or alkyl optionally substituted by nitro, Haloalkyl, and aryl;

R _A and R _B are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or

R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or

R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups;

R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ;

R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R 1') -X 1 -Y 1 -R 4 , And -N (R ₁ ′) -X ₁ -R _5b ,

R ₂ is selected from the group consisting of _{-R 4, -XR 4, -XYR 4} , and -XR _5;

R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ ;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene or heterocyclylene May be optionally interrupted or terminated by and optionally interrupted by one or more -O- groups;

X ₁ is C _{2 -20} alkylene;

,

,

,

, 및

로 이루어진 군으로부터 선택되고;Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O ) -O-, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ )- Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And

It is selected from the group consisting of;

로 이루어진 군으로부터 선택되고;Y ₁ is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q-, -C (R ₆ ) -N ( R ₈ )-, -OC (R ₆ ) -N (R ₈ )-, and

It is selected from the group consisting of;

Z is a bond or -O-;

R ₁ 'is selected from hydrogen, C _{1 -20} alkyl, hydroxy -C _{2 -20} alkylenyl, and alkoxy -C _{2 -20} group consisting of alkylenyl;

R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero The aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy , Heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and (alkyl, alkenyl, alkynyl, and heterocyclyl in case of) May be substituted by one or more substituents independently selected from the group consisting of oxo;

및

로 이루어진 군으로부터 선택되고;R ₅ is

And

It is selected from the group consisting of;

로 이루어진 군으로부터 선택되고;R _5b is

It is selected from the group consisting of;

R ₆ is selected from the group consisting of = O and = S;

R ₇ is C _{2 -7} alkylene;

R ₈ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;

R ₉ is selected from the group consisting of hydrogen and alkyl;

R ₁₀ is C _{3 -8} alkylene;

A is selected from the group consisting of -O-, -C (O)-, -S (O) _0-2- , and -N (R ₄ )-;

A 'is -O-, -S (O) _0-2 - it is selected from the group consisting _{of, -N (-QR 4) - -} , and -CH _2;

Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group;

V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;

V 'is selected from the group consisting of -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;

W is selected from the group consisting of a bond, -C (O)-, and -S (O) _2- ;

a and b are the integers of 1-6 independently, provided a + b is 7 or less.

The ring formation reaction is unpredictable because the L group is replaced without a strong electron withdrawing group adjacent to the L group.

In another embodiment, the method (i) provides a compound of Formula III, and the compound of Formula III is a carboxyl of formula hal-C (O) -R ₂ , wherein hal is chloro or bromo. Reacting with an acid halide, or anhydrides of formula O (—C (O) —R ₂ ) ₂ , or mixed anhydrides, to provide a compound of formula (IV).

In another embodiment, the method (ii) further comprises the step of providing a compound of formula II, and reducing the compound of formula II to provide a compound of formula III. .

In another embodiment, the method (ii) further comprises providing a compound of Formula VI and converting the hydroxy group at the 4-position of Formula VI to the L group to provide a compound of Formula III Provide (iv).

In another embodiment, the method (i) further comprises providing a compound of Formula VII and converting the hydroxy group at the 4-position of Formula VII to the L group to provide a compound of Formula IV Provide (v).

In another embodiment, the method (v) provides a compound of Formula VI, and the compound of Formula VI is a carboxylic acid of Formula hal-C (O) -R ₂ , wherein hal is chloro or bromo And reacting with an halide, or anhydride of formula O (—C (O) —R ₂ ) ₂ , or mixed anhydride, to provide a compound of formula (VII).

<Formula VI>

In another embodiment, the method (iv) or (vi) each further comprises providing a compound of Formula V and reducing the compound of Formula V to provide a compound of Formula VI (vii Or (viii).

In one embodiment, providing a compound of Formula VIII, reacting a compound of Formula VIII with an amine of Formula R ₁ NH ₂ , or a 1H-imidazo [4,5-c] pyridine or analog thereof of Formula I, or a pharmaceutical thereof Process (ix) is provided comprising providing a phase acceptable salt.

<Formula VIII>

<Formula I>

In the formula,

E is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -OS (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is alkyl Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by halo, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl Or; or

E combines with adjacent pyridine nitrogen atoms of Formulas I and VIII to form a ring with fused tetrazole in Formulas I-1 and IX;

<Formula I-1>

L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -OS (O) ₂ -R 'wherein R' is alkyl, halo, or alkyl optionally substituted by nitro , Haloalkyl, and aryl;

R _A and R _B are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or

R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or

R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups;

R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ;

R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R 1') -X 1 -Y 1 -R 4 , And -N (R ₁ ′) -X ₁ -R _5b ,

R ₂ is hydrogen;

R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ ;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene or heterocyclylene Optionally interrupted by or terminated by one or more optionally interrupted by one or more -O- groups;

X ₁ is C _{2 -20} alkylene;

,

,

,

, 및

로 이루어진 군으로부터 선택되고;Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O ) -O-, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ )- Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And

It is selected from the group consisting of;

으로 이루어진 군으로부터 선택되고;Y ₁ is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q-, -C (R ₆ ) -N ( R ₈ )-, -OC (R ₆ ) -N (R ₈ )-, and

It is selected from the group consisting of;

Z is a bond or -O-;

R ₁ 'is selected from hydrogen, C _{1 -20} alkyl, hydroxy -C _{2 -20} alkylenyl, and alkoxy -C _{2 -20} group consisting of alkylenyl;

R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero The aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy , Heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and (alkyl, alkenyl, alkynyl, and heterocyclyl in case of) May be substituted by one or more substituents independently selected from the group consisting of oxo;

, 및

로 이루어진 군으로부터 선택되고;R ₅ is

, And

It is selected from the group consisting of;

로 이루어진 군으로부터 선택되고:R _5b is

Is selected from the group consisting of:

R ₆ is selected from the group consisting of = O and = S;

R ₇ is C _{2 -7} alkylene;

R ₈ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;

R ₉ is selected from the group consisting of hydrogen and alkyl;

R ₁₀ is C _{3 -8} alkylene;

R ₁₁ and R ₁₂ are independently is C _{1 -4} alkyl, or R ₁₁ and R ₁₂ is -O-, -N (C _{1 -4} alkyl), together with the nitrogen atom to which they are attached - a, or -S-, optionally To form 5- or 6-membered rings containing;

A is selected from the group consisting of -O-, -C (O)-, -S (O) _0-2- , and -N (R ₄ )-;

A 'is -O-, -S (O) _0-2 - it is selected from the group consisting _{of, -N (-QR 4) - -} , and -CH _2;

Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group;

V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;

V 'is selected from the group consisting of -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;

W is selected from the group consisting of a bond, -C (O)-, and -S (O) _2- ;

a and b are the integers of 1-6 independently, provided a + b is 7 or less.

The ring formation reaction is also unpredictable because the L group is replaced without a strong electron withdrawing group adjacent to the L group.

In another embodiment, method (ix) provides method (x), further comprising forming an intermediate of Formula XI after reacting a compound of Formula VIII with an amine of Formula R ₁ NH ₂ .

<Formula XI>

In another embodiment, the method (xi) is provided wherein after reacting the compound of formula VIII with the amine of formula R ₁ NH ₂ in method (x), the intermediate of formula XI is isolated.

In another embodiment, the method (ix) or (x) each provides a compound of Formula VI, converts the hydroxy group at the 4-position to an L group, and the amino group at the 3-position is of the formula HC (O)- Process (xii) or (xiii) is further provided by reacting with formamide of N (R ₁₁ ) R ₁₂ to provide a compound of formula VIII.

<Formula VI>

In another embodiment, the method (xii) or (xv) is provided in the above method (xii) or (xiii), wherein the compound of formula VIII is provided without isolation before reacting with an amine of formula R ₁ NH ₂ , respectively. do.

In one embodiment, a method (xvi) is provided comprising providing a compound of Formula (XI) and forming a 1H-imidazo [4,5-c] pyridine or analog thereof, or a pharmaceutically acceptable salt thereof to provide.

<Formula XI>

<Formula I>

In the formula,

E is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -OS (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is alkyl Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by halo, or nitro, and Bn is from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl Selected; or

E combines with adjacent pyridine nitrogen atoms of Formulas I and XI to form a ring with a fused tetrazole in Formulas I-1 and XIII;

<Formula I-1>

L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -OS (O) ₂ -R ', wherein R' is alkyl, halo, or alkyl optionally substituted by nitro, Haloalkyl, and aryl;

R _A and R _B are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or

R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or

R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups;

R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ;

R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R 1') -X 1 -Y 1 -R 4 And -N (R ₁ ′) -X ₁ -R _5b ;

R ₂ is hydrogen;

R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ ;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene or heterocyclylene May be optionally interrupted or terminated by and optionally interrupted by one or more -O- groups;

X ₁ is C _{2 -20} alkylene;

,

,

,

, 및

로 이루어진 군으로부터 선택되고;Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O ) -O-, -N (R ₈ )-Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ )- Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And

It is selected from the group consisting of;

로 이루어진 군으로부터 선택되고;Y ₁ is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q-, -C (R ₆ ) -N ( R ₈ )-, -OC (R ₆ ) -N (R ₈ )-, and

It is selected from the group consisting of;

Z is a bond or -O-;

R ₁ 'is selected from hydrogen, C _{1 -20} alkyl, hydroxy -C _{2 -20} alkylenyl, and alkoxy -C _{2 -20} group consisting of alkylenyl;

R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero The aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy , Heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and (alkyl, alkenyl, alkynyl, and heterocycle In case of reel ) May be substituted by one or more substituents independently selected from the group consisting of oxo;

, 및

로 이루어진 군으로부터 선택되고;R ₅ is

, And

It is selected from the group consisting of;

로 이루어진 군으로부터 선택되고;R _5b is

It is selected from the group consisting of;

R ₆ is selected from the group consisting of = O and = S;

R ₇ is C _{2 -7} alkylene;

R ₈ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;

R ₉ is selected from the group consisting of hydrogen and alkyl;

R ₁₀ is C _{3 -8} alkylene;

A is selected from the group consisting of -O-, -C (O)-, -S (O) _0-2- , and -N (R ₄ )-;

A 'is -O-, -S (O) _0-2 - it is selected from the group consisting _{of, -N (-QR 4) - -} , and -CH _2;

Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group;

V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;

V 'is selected from the group consisting of -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;

W is selected from the group consisting of a bond, -C (O)-, and -S (O) _2- ;

a and b are the integers of 1-6 independently, provided a + b is 7 or less.

The ring formation reaction is also unpredictable because the L group is replaced without a strong electron withdrawing group adjacent to the L group.

In another embodiment, the method (xvi) provides a compound of Formula VI and converts the hydroxy group at the 4-position to an L group and the amino group at the 3-position is of the formula HC (O) —NH (R _And (xvii), further comprising reacting with formamide of ₁ ) to provide a compound of formula XI.

<Formula VI>

In another embodiment, a method (xviii) is provided in said method (xvii), wherein said compound of formula (XI) is provided without isolation before forming said compound of formula (I).

In another embodiment, the method (xii), (xiii), (xiv), (xv), (xvii), or (xviii) provides a compound of Formula V and the compound of Formula V is reduced to It provides a method (xix), (xx), (xxi), (xxii), (xxiii), or (xxiv) further comprising providing a compound.

<Formula V>

In another embodiment, methods (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), (xxiii), or ( xxiv) further comprising converting E in the amino group to an amino group in the compound of formula (I) to provide a compound of formula (X) or a pharmaceutically acceptable salt thereof (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii-1), (ix-1), (x-1), (xi -1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1), (xvii-1), (xviii-1), (xix-1 ), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1).

<Formula X>

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1) Wherein E is hydrogen and the compound of formula (I) is a compound of formula (I-2) wherein the conversion of hydrogen to an amino group in the compound of formula (I-2) involves oxidizing the compound of formula (I-2) to 5N- Providing an oxide and aminating the compound of formula (XX) to provide a compound of formula (X), or a pharmaceutically acceptable salt thereof (i-2), (ii-2), (iii- 2), (iv-2), (v-2), (vi-2), (vii-2), (viii-2), (ix-2), (x-2), (xi-2) , (xii-2), (xiii-2), (xiv-2), (xv-2), (xvi-2), (xvii-2), (xviii-2), (xix-2), ( xx-2), (xxi-2), (xxii-2), (xxiii-2), or (xxiv-2).

[Formula I-2]

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1) Wherein E is Hal, and the compound of formula (I) is a compound of formula (I-3), wherein converting the Hal group to an amino group in the compound of formula (I-3) comprises amination of the compound of formula (I-3) Or providing a pharmaceutically acceptable salt thereof (i-3), (ii-3), (iii-3), (iv-3), (v-3), (vi-) 3), (vii-3), (viii-3), (ix-3), (x-3), (xi-3), (xii-3), (xiii-3), (xiv-3) , (xv-3), (xvi-3), (xvii-3), (xviii-3), (xix-3), (xx-3), (xxi-3), (xxii-3), ( xxiii-3), or (xxiv-3).

[Formula I-3]

Wherein Hal is fluoro, chloro, bromo, or iodo.

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1) Wherein E is hydroxy and the compound of formula (I) is a compound of formula (I-4) wherein the step of converting a hydroxy group to an amino group in the compound of formula (I-4) is a hydroxy group at the 4-position of formula (I-4) Converting to a group to provide a compound or salt of formula (I-3) and aminating the compound of formula (I-3) to provide a compound of formula (X), or a pharmaceutically acceptable salt thereof (i-4 ), (ii-4), (iii-4), (iv-4), (v-4), (vi-4), (vii-4), (viii-4), (ix-4), (x-4), (xi-4), (xii-4), (xiii-4), (xiv-4), (xv-4), (xvi-4), (xvii-4), (xviii -4), (xix-4), (xx-4), (xxi-4), (xxii-4), (xxiii-4), or (xxiv-4).

[Formula I-4]

<Formula I-3>

Wherein Hal is fluoro, chloro, bromo, or iodo.

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1) Wherein E is hydroxy and the compound of formula (I) is a compound of formula (I-4) wherein the step of converting a hydroxy group to an amino group in the compound of formula (I-4) comprises the formula hal-S (O) ₂ , hal is chloro or bromo), or by sulfonating a compound of formula I-4 by reacting with a compound of formula O (-S (O) ₂ -R ') ₂ to provide a compound of formula I-5 Replacing the -OS (O) ₂ -R 'group in I-5 with an amino group of formula -N (Bn) ₂ to provide a compound of formula I-6, and removing the Bn protecting group of formula I-6 to remove a compound of formula X Or providing a pharmaceutically acceptable salt thereof (i-5), (ii-5), ( iii-5), (iv-5), (v-5), (vi-5), (vii-5), (viii-5), (ix-5), (x-5), (xi- 5), (xii-5), (xiii-5), (xiv-5), (xv-5), (xvi-5), (xvii-5), (xviii-5), (xix-5) , (xx-5), (xxi-5), (xxii-5), (xxiii-5), or (xxiv-5).

<Formula I-4>

[Formula I-5]

[Formula I-6]

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1) Wherein E is phenoxy and the compound of formula (I) is a compound of formula (I-7) and the step of converting the phenoxy group to an amino group in the compound of formula (I-7) comprises amination of the compound of formula (I-7) To provide a compound of, or a pharmaceutically acceptable salt thereof (i-6), (ii-6), (iii-6), (iv-6), (v-6), ( vi-6), (vii-6), (viii-6), (ix-6), (x-6), (xi-6), (xii-6), (xiii-6), (xiv- 6), (xv-6), (xvi-6), (xvii-6), (xviii-6), (xix-6), (xx-6), (xxi-6), (xxii-6) , (xxiii-6), or (xxiv-6).

[Formula I-7]

In the formula, Ph is phenyl.

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxxiv-1) Wherein E is -OS (O) ₂ -R ', the compound of formula I is a compound of formula I-5, and the -OS (O) ₂ -R' group is converted to an amino group in the compound of formula (A) replaces the -OS (O) ₂ -R 'group with an amino group of the formula -N (Bn) ₂ to provide a compound of formula (I-6), removes the Bn protecting group from formula (I-6), or (I-7), (ii-7), (iii-7), (iv-7), (v-7), (vi-7), comprising providing a pharmaceutically acceptable salt thereof. , (vii-7), (viii-7), (ix-7), (x-7), (xi-7), (xii-7), (xiii-7), (xiv-7), ( xv-7), (xvi-7), (xvii-7), (xviii-7), (xix-7), (xx-7), (xxi-7), (xxii-7), (xxiii- 7), or (xxiv-7).

<Formula I-5>

<Formula I-6>

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1) Wherein E is —N (Bn) ₂ , the compound of formula I is a compound of formula I-6, and the step of converting the —N (Bn) ₂ group to an amino group in the compound of formula I-6, removes the Bn protecting group. To provide a compound of formula (X), or a pharmaceutically acceptable salt thereof (i-8), (ii-8), (iii-8), (iv-8), (v-8) ), (vi-8), (vii-8), (viii-8), (ix-8), (x-8), (xi-8), (xii-8), (xiii-8), (xiv-8), (xv-8), (xvi-8), (xvii-8), (xviii-8), (xix-8), (xx-8), (xxi-8), (xxii -8), (xxiii-8), or (xxiv-8).

<Formula I-6>

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1) In which E combines with an adjacent pyridine nitrogen atom of Formula (I) to form a ring with a fused tetrazole of Formula (I-1), and converting the ring to an amino group in the compound of Formula (I-1) with a compound of Formula (I-1) Reacting the compound with triphenylphosphine to provide a compound of formula XXI, and hydrolyzing the compound of formula XXI to provide a compound of formula X, or a pharmaceutically acceptable salt thereof ( i-9), (ii-9), (iii-9), (iv-9), (v-9), (vi-9), (vii-9), (viii-9), (ix- 9), (x-9), (xi-9), (xii-9), (xiii-9), (xiv-9), (xv-9), (xvi-9), (xvii-9) , (xviii-9), (xix-9), (xx-9), (xxi-9), (xxii-9), (xxiii-9), and Provides (xxiv-9).

<Formula I-1>

<Formula XXI>

In other embodiments, methods (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii -1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1) ), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1) In which E combines with an adjacent pyridine nitrogen atom of Formula (I) to form a ring with a fused tetrazole in Formula (I-1), and converting the ring to an amino group with a fused tetrazole in compound (I-1) Reductively removing the ring with a tetrazole from a compound of (i-10), (ii-10), (iii-10) to provide a compound of formula (X), or a pharmaceutically acceptable salt thereof. ), (iv-10), (v-10), (vi-10), (vii-10), (viii-10), (ix-10), (x-10), (xi-10), (xii-10), (xiii-10), (xiv-10), (xv-10), (xvi-10), (xvii-10), (xviii-10), (xix-10), (xx -10), (xxi-10), (xxii-10), (xxiii-10), or (xxiv-10).

<Formula I-1>

In another embodiment, the present invention provides an intermediate compound of formula (XI) or a pharmaceutically acceptable salt thereof.

<Formula XI>

In the formula,

E is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -OS (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is alkyl Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by halo, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl Or; or

E combines with an adjacent pyridine nitrogen atom of formula (XI) to form a ring with a fused tetrazole in formula (XIII)

<Formula XIII>

L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -OS (O) ₂ -R ', wherein R' is alkyl, halo, or alkyl optionally substituted by nitro, Haloalkyl, and aryl;

R _A and R _B are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or

R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or

R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups;

R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ;

R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R 1') -X 1 -Y 1 - R 4 And -N (R ₁ ′) -X ₁ -R _5b ;

R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ ;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene or heterocyclylene May be optionally interrupted or terminated by and optionally interrupted by one or more -O- groups;

X ₁ is C _{2 -20} alkylene;

,

,

,

, 및

로 이루어진 군으로부터 선택되고;Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O ) -O-, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ )- Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And

It is selected from the group consisting of;

로 이루어진 군으로부터 선택되고;Y ₁ is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q-, -C (R ₆ ) -N ( R ₈ )-, -OC (R ₆ ) -N (R ₈ )-, and

It is selected from the group consisting of;

Z is a bond or -O-;

R ₁ 'is selected from hydrogen, C _{1 -20} alkyl, hydroxy -C _{2 -20} alkylenyl, and alkoxy -C _{2 -20} group consisting of alkylenyl;

R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero The aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy , Heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and (alkyl, alkenyl, alkynyl, and heterocyclyl in case of) May be substituted by one or more substituents independently selected from the group consisting of oxo;

, 및

로 이루어진 군으로부터 선택되고;R ₅ is

, And

It is selected from the group consisting of;

로 이루어진 군으로부 터 선택되고;R _5b is

Is selected from the group consisting of;

R ₆ is selected from the group consisting of = O and = S;

R ₇ is C _{2 -7} alkylene;

R ₈ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;

R ₉ is selected from the group consisting of hydrogen and alkyl;

R ₁₀ is C _{3 -8} alkylene;

A is selected from the group consisting of -O-, -C (O)-, -S (O) _0-2- , and -N (R ₄ )-;

A 'is -O-, -S (O) _0-2 - it is selected from the group consisting _{of, -N (-QR 4) - -} , and -CH _2;

Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) S-, and -C (R ₆ ) -N (OR ₉ )- Is selected from;

V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;

V 'is selected from the group consisting of -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;

W is selected from the group consisting of a bond, -C (O)-, and -S (O) _2- ;

a and b are the integers of 1-6 independently, provided a + b is 7 or less.

For certain embodiments, including any one of the above embodiments, R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R ₁ ') -X ₁ -Y ₁ -R ₄ , and -N (R ₁ ') -X ₁ -R _5b .

For certain embodiments, including any one of the above embodiments, R ₁ is selected from the group consisting of _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, and -XR _5.

For certain embodiments, including any one of the above embodiments, R ₁ is -R ₄ or -XR ₄ . For certain of these embodiments, -R ₄ consists of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,2-dimethyl-4-oxopentyl, and (1-hydroxycyclobutyl) methyl Selected from the group. For certain of these embodiments, R ₁ is -R ₄ and -R ₄ is 2-methylpropyl or 2-hydroxy-2-methylpropyl. For certain of these embodiments, R ₁ is -R ₄ and -R ₄ is 2-methylpropyl. Alternatively, for certain of these embodiments, R ₁ is -XR ₄ and -XR ₄ is 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl.

For certain embodiments, including any one of the above embodiments, the R ₁ is -R ₄ or -XR _4, except for the embodiments, R ₁ is ₄ -XYR. For certain embodiments of these, X is a C _{2 -4} alkylene, Y is -S (O) ₂ - or -N (R ₈₎ a -Q-. For certain of these embodiments, -XYR ₄ is 2- (propylsulfonyl) ethyl, 2-methyl-2-[(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and 2- ( Acetylamino) -2-methylpropyl.

For certain embodiments, including any one of the above embodiments, R ₁ is -R _4, -XR _4, or -XYR with the exception of ₄ embodiments, R ₁ is -XR _5. For certain of these embodiments, -XR ₅ is 4-[(morpholin-4-ylcarbonyl) amino] butyl.

For certain embodiments, including any one of the above embodiments, R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, or -XR, except for the _five embodiments, R ₁ is -N (R ₁ ') -QR ₄ , -N (R ₁ ') -X ₁ -Y ₁ -R ₄ , and -N (R ₁ ') -X ₁ -R _5b .

For certain embodiments, including any one of the above embodiments, with the exception of the embodiment of R ₂ is hydrogen, R ₂ is the group consisting of _{-R 4, -XR 4, -XYR 4} , ₅ and -XR Is selected from.

For certain embodiments, including any one of the above embodiments except for the excluded embodiments, R ₂ is -R ₄ . For certain of these embodiments, R ₂ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl. For certain of these embodiments, R ₂ is selected from the group consisting of hydrogen, methyl, ethyl, and ethoxymethyl. For certain embodiments, R ₂ is hydrogen.

For certain embodiments, including any one of the above embodiments, R _A and R _B are each independently from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ Selected from; or

R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or

R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups.

For certain embodiments, including any one of the above embodiments, R _A and R _B are each independently from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ Is selected. For certain of these embodiments, R _A and R _B are each methyl.

For certain embodiments, R _A and R _B are, as well as any one of the embodiments that can form a fused benzene ring together, and R _A and R _B may form a fused benzene ring together, in which the benzene ring is Beach Or substituted by one R group, substituted by one R ₃ group, or substituted by one R group and one R ₃ group. For certain of these embodiments, R is hydroxy or bromo and R ₃ is methoxy, phenoxy, or benzyloxy. For certain of these embodiments, the fused benzene ring is substituted by one R group selected from the group consisting of hydroxy and bromo. Alternatively, for certain of these embodiments, the fused benzene ring is substituted by one R ₃ group, where R ₃ is methoxy, phenoxy, or benzyloxy. For certain embodiments, R _A and R _B together form a fused benzene ring, wherein the benzene ring is unsubstituted.

이고, 식 중, 굵게 표시된 결합은 고리가 융합된 위치를 나타낸다. 이들 중 특정 실시양태에 대해, R은 히드록시 또는 브로모이고, R₃은 메톡시, 페녹시, 또는 벤질옥시이다. 이들 중 특정 실시양태에 대해, 융합 피리딘 고리는 히드록시 및 브로모로 이루어진 군으로부터 선택된 1개의 R기에 의해 치환된다. 다르게는, 이들 중 특정 실시양태에 대해, 융합 피리딘 고리는 1개의 R₃기에 의해 치환되고, 여기서 R₃은 메톡시, 페녹시, 또는 벤질옥시이다. 특정 실시 양태에 대해, R_A 및 R_B는 함께 비치환된 융합 피리딘 고리를 형성하며, 여기서 융합 피리딘 고리는

이고, 식 중, 굵게 표시된 결합은 고리가 융합된 위치를 나타낸다.For certain embodiments, including any one of the above embodiments which R _A and R _B may form a fused pyridine ring together, and R _A and R _B may form a fused pyridine ring together, where fused pyridine ring is Unsubstituted or substituted by one R group, substituted by one R ₃ group, or substituted by one R group and one R ₃ group, wherein the fused pyridine ring is

Wherein the bond in bold represents the position where the ring is fused. For certain of these embodiments, R is hydroxy or bromo and R ₃ is methoxy, phenoxy, or benzyloxy. For certain of these embodiments, the fused pyridine ring is substituted by one R group selected from the group consisting of hydroxy and bromo. Alternatively, for certain of these embodiments, the fused pyridine ring is substituted by one R ₃ group, where R ₃ is methoxy, phenoxy, or benzyloxy. For certain embodiments, R _A and R _B together form an unsubstituted fused pyridine ring, wherein the fused pyridine ring is

Wherein the bond in bold represents the position where the ring is fused.

이고, 여기서 고리는 비치환되며; 굵게 표시된 결합은 고리가 융합된 위치를 나타낸다.For certain embodiments, R _A and R _B together optionally contain one nitrogen atom, including any one of the above embodiments wherein R _A and R _B may together form a fused 5- to 7-membered saturated ring To form a fused 5- to 7-membered saturated ring wherein the fused ring is unsubstituted or substituted by one or more R groups. For certain of these embodiments, R _A and R _B together form a fused 5- to 7-membered carbocyclic ring, wherein the fused ring is unsubstituted or substituted by one or more R groups. For certain of these embodiments, the fused ring is an unsubstituted 6 membered carbocyclic ring. Alternatively, for certain of these embodiments, R _A and R _B together form a fused 5- to 7-membered saturated ring containing one nitrogen atom, wherein the fused ring is unsubstituted, or at least one R group It is substituted by. For certain of these embodiments, the fused ring is a fused 6 membered ring, which is unsubstituted or substituted by one or more R groups at the carbon atom. For certain of these embodiments, the fused six-membered ring is

Wherein the ring is unsubstituted; The bond in bold indicates the position where the ring is fused.

For certain embodiments, methods (i) through (viii), methods (i-1) through (viii-1), methods (i-2) through (viii-2), methods (i-3) through (viii) -3), methods (i-4) to (viii-4), methods (i-5) to (viii-5), methods (i-6) to (viii-6), methods (i-7) to of the above embodiments of (viii-7), methods (i-8) to (viii-8), methods (i-9) to (viii-9), and methods (i-10) to (viii-10) Including any one, R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , wherein

R _A1 and R _B1 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or

R _A1 and R _B1 together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted, substituted by one R _a group, substituted by one R _3a group, or one Substituted by _a R _a group and one R _3a group; or

R _A1 and R _B1 together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R _a groups;

R _a is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, trifluoromethyl, alkoxy, alkylthio, and —N (R ₉ ) ₂ ;

R _1a is -R _4a , -XR _4a , -XY _a -R _4a , -XY _a -XY _a -R _4a , -XR _5a , -N (R ₁ ') -QR _4a , -N (R ₁ ') -X ₁ -Y ₁ -R _4a , and -N (R ₁ ′) -X ₁ -R _5b ;

R _2a is selected from the group consisting of _{-R 4a, -XR 4a, -XY a} -R 4a, and -XR _5a;

R _3a is selected from the group consisting of -ZR _4a , -ZXR _4a , -ZXY _a -R _4a , -ZXY _a -XY _a -R _4a , and -ZXR _5a ;

,

,

,

, 및

로 이루어진 군으로부터 선택되고;Y _a is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-,

,

,

,

, And

It is selected from the group consisting of;

R _4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero Aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyl Independently selected from the group consisting of lenoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, and (dialkylamino) alkyleneoxy Substituted by one or more substituents;

로 이루어진 군으로부터 선택된다.R _5a is

It is selected from the group consisting of.

For each resulting embodiment, if present,

Formula I is Formula I _a ;

[Formula I _a ]

Formula I-1 is Formula I _a- 1;

Formula I _a -1]

Formula I-2 is Formula I _a -2;

[Formula I _a -2]

Formula I-3 is Formula I _a -3;

Formula I _a -3]

Formula I-4 is Formula I _a- 4;

Formula I _a -4]

Formula I-5 is Formula I _a -5;

Formula I _a -5]

Formula I-6 is Formula I _a- 6;

Formula I _a- 6

Formula I-7 is Formula I _a -7;

Formula I _a -7]

Formula II is Formula II _a ;

[Formula II _a ]

Formula III is Formula III _a ;

[Formula III _a ]

Formula IV is Formula IV _a ;

[Formula IV _a ]

Formula IV-1 is Formula IV _a- 1;

Formula IV _a -1]

Formula V is of formula V _a ;

[Formula V _a ]

Formula VI is Formula VI _a ;

Formula VI _a

Formula VII is formula VII _a

Formula VII _a ]

For certain consequent embodiments, when present,

Formula X is Formula X _a ;

[Formula X _a ]

Formula XX is the following formula XX _a ;

[Formula XX _a ]

Formula XXI is formula XXI _a

Formula XXI _a

For certain embodiments, methods (ix) to (xxiv), methods (ix-1) to (xxiv-1), methods (ix-2) to (xxiv-2), methods (ix-3) to (xxiv) -3), methods (ix-4) to (xxiv-4), methods (ix-5) to (xxiv-5), methods (ix-6) to (xxiv-6), methods (ix-7) to of the above embodiments of (xxiv-7), methods (ix-8) to (xxiv-8), methods (ix-9) to (xxiv-9), and methods (ix-10) to (xxiv-10) Including any one, R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is hydrogen, wherein R _A1 , R _B1 , and R _1a are R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a and R ₂ is R _2a as defined above. For the resulting embodiments of Formulas I _a , I _a -2, I _a -3, I _a -4, I _a -5, I _a -6, and I _a -7, R _2a is hydrogen. For the resulting embodiments of formulas X _a , XX _a , and XXI _a , R _2a is hydrogen.

For certain embodiments, including any one of the above embodiments of Formula XI, R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , wherein R _A1 , R _B1 , and R _1a Is as defined above for embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , and R ₂ is R _2a .

For each resulting embodiment, if present,

Formula VIII is Formula VIII _a ;

[Formula VIII _a ]

Formula IX is formula IX _a ;

[Formula IX _a ]

Formula XI is formula XI _a ;

Formula XI _a

Formula XIII is formula XIII _a

[Formula XIII _a ]

For each resulting embodiment, when present, R is R _a , R ₃ is R _3a , R ₄ is R _4a , R ₅ is R _5a , and Y is Y _a .

For certain embodiments, R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 , and R ₁ is R _1a, R ₂ is an exemplary embodiment hydrogen, and including any one of the embodiments of formula XI _{a, 1a} R is _{-R 4a, -XR 4a, -XY a} -R 4a, -XY _a -XY _a -R _4a , -XR _5a , -N (R ₁ ') -QR _4a , -N (R ₁ ') -X ₁ -Y ₁ -R _4a , and -N (R ₁ ') -X ₁ -R _5b .

For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 , and R ₁ is R _1a, R ₂ is an exemplary embodiment hydrogen, and including any one of the embodiments of formula XI _{a, 1a} R is _{-R 4a, -XR 4a, -XY a} -R 4a, -XY _a -XY _a -R _4a , and -XR _5a .

For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 R _1a is —R _4a or —XR _4a , including any one of embodiments wherein R ₁ is R _1a and R ₂ is hydrogen, and embodiments of Formula XI _a . For certain of these embodiments, -R _4a is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, and (1-hydroxycyclobutyl) methyl, -XR _4a is 2, 2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. For certain of these embodiments, R _1a is —R _4a and —R _4a is 2-methylpropyl or 2-hydroxy-2-methylpropyl. For certain of these embodiments, R _1a is —R _4a and —R _4a is 2-methylpropyl. Alternatively, for certain of these embodiments, R _1a is —XR _4a and —XR _4a is 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl.

For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a, and R ₂ is hydrogen exemplary embodiments, and formula (XI) of the embodiments of _a, as well as any one of, R _1a and is a, R _1a, except the embodiment of -R _4a or _4a -XR Is -XY _a -R _4a . For certain embodiments of these, X is a C _{2 -4} alkylene, Y is _a -S (O) ₂ - or -N (R ₈₎ a -Q-. For certain of these embodiments, -XY _a -R _4a is 2- (propylsulfonyl) ethyl, 2-methyl-2-[(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and 2 -(Acetylamino) -2-methylpropyl.

For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 , Embodiments wherein R _1a is —R _4a , —XR _4a , or —XY _a —R _4a , including any one of embodiments of Formula XI _a , wherein R ₁ is R _1a and R ₂ is hydrogen. Except, R _1a is —XR _5a . For certain of these embodiments, -XR _5a is 4- [(morpholin-4-ylcarbonyl) amino] butyl.

For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a, R ₂ is an exemplary embodiment hydrogen, and including any one of the embodiments of formula XI _a, R a _1a -R _4a, and _{-XR 4a, -XY a -R 4a,} -XY Except for embodiments where _a -XY _a -R _4a , or -XR _5a , R _1a is -N (R ₁ ′) -QR _4a , -N (R ₁ ′) -X ₁ -Y ₁ -R _4a , And -N (R ₁ ′) -X ₁ -R _5b .

For certain embodiments, including any one of the preceding embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , and R ₂ is R _2a , R _2a is -R _4a , -XR _4a , -XY _a -R _4a , and -XR _5a .

For certain embodiments, R _2a is —R _4a , including any one of the preceding embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , and R ₂ is R _2a . For certain of these embodiments, R _2a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl. For certain of these embodiments, R _2a is selected from the group consisting of hydrogen, methyl, ethyl, and ethoxymethyl.

For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 R _A1 and R _B1 are each hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, including any one of embodiments of Formula XI _a , wherein R ₁ is R _1a and R ₂ is hydrogen. And and -N (R ₉ ) ₂ independently; or

R _A1 and R _B1 together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted, substituted by one R _a group, substituted by one R _3a group, or one Substituted by _a R _a group and one R _3a group; or

R _A1 and R _B1 together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R _a groups.

For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a, and the R ₂ is hydrogen this embodiment, and including any one of the embodiments of formula XI _a, R _A1 and R _B1 are each hydrogen, halogen, alkyl, alkenyl, alkoxy, alkyl Thio, and -N (R ₉ ) ₂ are independently selected. For certain of these embodiments, R _A1 and R _B1 are each methyl.

For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a, and exemplary R ₂ is hydrogen embodiments, and formula XI embodiment of _a embodiments, R _A1 and R _B1, as well as any one of the embodiments that can form a fused benzene ring together, R _A1 And R _B1 together form a fused benzene ring, wherein the benzene ring is unsubstituted or substituted by one R _a group, substituted by one R _3a group, one R _a group and one R _3a Substituted by a group. For certain of these embodiments, R _a is hydroxy or bromo and R _3a is methoxy, phenoxy, or benzyloxy. For certain of these embodiments, the fused benzene ring is substituted by one R _a group selected from the group consisting of hydroxy and bromo. Alternatively, for certain of these embodiments, the fused benzene ring is substituted by one R _3a group, where R _3a is methoxy, phenoxy, or benzyloxy. For certain embodiments, R _A1 and R _B1 together form an unsubstituted fused benzene ring.

이고, 식 중, 굵게 표시된 결합은 고리가 융합된 위치를 나타낸다. 이들 중 특정 실시양태에 대해, R_a은 히드록시 또는 브로모이고, R_3a 는 메톡시, 페녹시, 또는 벤질옥시이다. 이들 중 특정 실시양태에 대해, 융합 피리딘 고리는 히드록시 및 브로모로 이루어진 군으로부터 선택된 1개의 R_a기에 의해 치환된다. 다르게는, 이들 중 특정 실시양태에 대해, 융합 피리딘 고리는 1개의 R_3a기에 의해 치환되고, 여기서 R_3a는 메톡시, 페녹시, 또는 벤질옥시이다. 다르게는, 이들 중 특정 실시양태에 대해, 융합 피리딘 고리는 비치환된다.For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R 1 is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a, and, R ₂ is, as well as a hydrogen in embodiments, any one of the embodiments in this embodiment, and R _A1 and R _B1 of formula XI _a to form a fused pyridine ring together embodiment, R _A1, and R _B1 together form a fused pyridine ring, wherein the fused pyridine ring is unsubstituted or substituted by one R _a group, substituted by one R _3a group, or on one R _a group and one R _3a group Substituted by; Where the fused pyridine ring is

Wherein the bond in bold represents the position where the ring is fused. For certain of these embodiments, R _a is hydroxy or bromo and R _3a is methoxy, phenoxy, or benzyloxy. For certain of these embodiments, the fused pyridine ring is substituted by one R _a group selected from the group consisting of hydroxy and bromo. Alternatively, for certain of these embodiments, the fused pyridine ring is substituted by one R _3a group, where R _3a is methoxy, phenoxy, or benzyloxy. Alternatively, for certain of these embodiments, the fused pyridine ring is unsubstituted.

이고, 여기서 고리는 비치환되며; 식 중, 굵게 표시된 결합은 고리가 융합된 위치를 나타낸다.For certain embodiments, the above embodiments wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , R _A is R _A1 , R _B is R _B1 Any _one of the embodiments wherein R ₁ is R _1a and R ₂ is hydrogen, an embodiment of Formula XI _a , and wherein R _A1 and R _B1 can together form a fused 5- to 7-membered saturated ring In addition, R _A1 and R _B1 together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R _a groups. For certain of these embodiments, R _A1 and R _B1 together form a fused 5- to 7-membered carbocyclic ring, wherein the fused ring is unsubstituted or substituted by one or more R _a groups. For certain of these embodiments, the fused ring is an unsubstituted 6 membered carbocyclic ring. Alternatively, for certain of these embodiments, R _A1 and R _B1 together form a fused 5- to 7-membered saturated ring containing one nitrogen atom, wherein the fused ring is unsubstituted or one or more R _a Substituted by a group. For certain of these embodiments, the fused ring is a fused 6 membered ring, which is unsubstituted or substituted by one or more R _a groups at a carbon atom. For certain of these embodiments, the fused six-membered ring is

Wherein the ring is unsubstituted; In the formula, the bold bond indicates the position at which the ring is fused.

For certain embodiments, including any one of the above embodiments comprising reacting a compound of Formula IV with an amine of Formula R ₁ NH ₂ , the step is performed at elevated temperature without solvent.

For certain embodiments, including any one of the above embodiments, including reacting a compound of Formula IV with an amine of Formula R _1a NH ₂ , wherein Formula IV is Formula IV _a , wherein the step is performed at elevated temperature without solvent To perform.

<Formula IV _a >

For certain embodiments, except for embodiments in which the step is carried out without solvent, including any one of the above embodiments comprising reacting a compound of Formula IV with an amine of Formula R ₁ NH ₂ At elevated temperature in a solvent. For certain of these embodiments, the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, tert-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone, and toluene . For certain of these embodiments, the solvent is selected from the group consisting of trifluoroethanol, isopropanol, and tert-butanol.

For certain embodiments, the step is carried out without solvent, including any one of the above embodiments, wherein Formula IV is of Formula IV _a and reacting the compound of Formula IV _{a with} an amine of Formula R _1a NH ₂ Except for the embodiment described, the step is carried out at elevated temperature in a solvent.

<Formula IV _a >

For certain of these embodiments, the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, tert-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone, and toluene. For certain of these embodiments, the solvent is selected from the group consisting of trifluoroethanol, isopropanol, and tert-butanol.

For certain embodiments, including any one of the above embodiments including reacting a compound of Formula VIII with an amine of Formula R ₁ NH ₂ , the step is performed without solvent. For certain of these embodiments, the amine is an amine of the formula R _1a NH ₂ . For certain of these embodiments, the step is performed at elevated temperature. For certain of these embodiments, the compound of formula VIII is _a compound of formula VIII _a .

For certain embodiments, the step is carried out in a solvent, including any one of the above embodiments including the step of reacting a compound of Formula VIII with an amine of Formula R ₁ NH ₂ . For certain of these embodiments, the solvent is from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, tert-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone, toluene, and tetrahydrofuran Is selected. For certain of these embodiments, the solvent is selected from the group consisting of trifluoroethanol, isopropanol, tert-butanol, and acetonitrile. For certain of these embodiments, the amine is an amine of the formula R _1a NH ₂ . For certain of these embodiments, the step is performed at elevated temperature. For certain other these embodiments, the step is performed at room temperature. For certain of these embodiments, the compound of formula VIII is _a compound of formula VIII _a .

For certain embodiments, including any one of the above embodiments including elevated temperatures, the elevated temperature is at least 80 ° C.

For certain embodiments, including any one of the above embodiments including elevated temperatures, the elevated temperature is at least 110 ° C.

For certain embodiments, including any one of the above embodiments including elevated temperatures, the elevated temperature is no greater than 200 ° C.

For certain embodiments, including any one of the above embodiments including elevated temperatures, the elevated temperature is no greater than 180 ° C.

For certain embodiments, including any one of the above embodiments including elevated temperatures, the elevated temperature is no greater than 165 ° C.

For certain embodiments, including any one of the above embodiments including elevated temperatures, the elevated temperature is no greater than 150 ° C.

For certain embodiments, including any one of the above embodiments including elevated temperatures, the elevated temperature is no greater than 135 ° C.

In one embodiment, the present invention provides a compound of formula IV:

<Formula IV>

Wherein R _A , R _B , R ₂ , E, and L are as defined above in method (i). For certain of these embodiments, R _A , R _B , R ₂ , E, and L are as defined in any one of the above embodiments of method (i).

In another embodiment, the present invention provides _a compound of Formula IV _a

<Formula IV _a >

Wherein R _A1 , R _B1 , R _2a , E, and L are as defined above in method (i) wherein R _A is R _A1 , R _B is R _B1 and R ₂ is R _2a . For certain of these embodiments, R _A1 , R _B1 , R _2a , E, and L are the above embodiments of method (i) wherein R _A is R _A1 , R _B is R _B1 , and R ₂ is R _2a As defined in any one of.

For certain embodiments, the method (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), or any of the above embodiments of Formula IV or IV _a Including any one, E is from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -0-S (O) ₂ -R ', and -N (Bn) ₂ Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by alkyl, halo, or nitro, and Bn is benzyl, p-methoxybenzyl, p-methylbenzyl, and 2- Is selected from the group consisting of furanylmethyl; Or E combines with an adjacent pyridine nitrogen atom to form a ring with the fused tetrazole shown in Formulas I-1 and IV-1.

<Formula I-1>

<Formula IV-1>

For certain embodiments, methods (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xix), (xx), (xxi), or (xxii) Including any one of the above embodiments of E), E is hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -0-S (O) ₂ -R ', and -N (Bn ) Is selected from the group consisting of ₂ , wherein R 'is selected from the group consisting of alkyl, halo, or nitro optionally substituted by alkyl, haloalkyl, and aryl, Bn is benzyl, p-methoxybenzyl, p- Methylbenzyl, and 2-furanylmethyl; or

E combines with adjacent pyridine nitrogen atoms of Formulas I and VIII to form a ring with fused tetrazole in Formulas I-1 and IX.

<Formula I-1>

<Formula IX>

For certain embodiments, including any one of the above embodiments of methods (xvi), (xvii), (xviii), (xxiii), and (xxiv), E is hydrogen, fluoro, chloro, bromo, Iodo, hydroxy, phenoxy, -0-S (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is optionally substituted by alkyl, halo, or nitro Alkyl, haloalkyl, and aryl; Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or

E combines with adjacent pyridine nitrogen atoms of Formulas (I) and (XI) to form a ring with a fused tetrazole in Formulas (I-1) and (XIII).

<Formula I-1>

<Formula XIII>

For certain embodiments, including any one of the above embodiments of Formula (XI) or (XI _a) , E is hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -0-S (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is selected from the group consisting of alkyl, halo, or nitro optionally substituted by alkyl, haloalkyl, and aryl, and Bn is Benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or

E combines with an adjacent pyridine nitrogen atom of Formula (XI) to form a ring with a fused tetrazole in Formula (XIII).

<Formula XIII>

For certain of these embodiments, E is hydrogen. Alternatively, for certain of these embodiments, E is fluoro, chloro, bromo, or iodo, and for certain of these embodiments, E is chloro. Alternatively, for certain of these embodiments, E is hydroxy. Alternatively, for certain of these embodiments, E is phenoxy (OPh). Alternatively, for certain of these embodiments, E is -0-S (O) ₂ -R 'wherein R' consists of alkyl, haloalkyl, and aryl optionally substituted by alkyl, halo, or nitro. Selected from the group. Alternatively, for certain of these embodiments, E is -N (Bn) ₂ , wherein Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl. Alternatively, for certain of these embodiments, E combines with adjacent pyridine nitrogen atoms to form a ring with fused tetrazole.

For certain embodiments, including any one of the above embodiments, L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -0-S (O) ₂ -R ' , Wherein R 'is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by alkyl, halo, or nitro. For certain embodiments, including any one of the above embodiments, L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -0-S (O) ₂ -R ' , Wherein R 'is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by alkyl or halo. For certain of these embodiments, L is fluoro, chloro, bromo, or iodo, and for certain of these embodiments, L is chloro. Alternatively, for certain of these embodiments, L is phenoxy. Alternatively, for certain of these embodiments, L is -0-S (O) ₂ -R 'wherein R' consists of alkyl, haloalkyl, and aryl optionally substituted by alkyl, halo, or nitro. Selected from the group. For certain of these embodiments, L is -0-S (O) ₂ -R 'wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by alkyl or halo.

For certain embodiments, including any one of the above embodiments wherein R 'is present, R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by alkyl, halo, or nitro. For certain embodiments, R 'is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by alkyl or halo. For certain of these embodiments, R 'is alkyl, and for certain of these embodiments, R' is methyl. Alternatively, for certain of these embodiments, R 'is haloalkyl, and for certain of these embodiments, R' is trifluoromethyl. Alternatively, for certain of these embodiments, R 'is aryl optionally substituted by alkyl or halo, and for certain of these embodiments, R' is phenyl, p-bromophenyl, or p-tolyl. For certain of these embodiments, R 'is aryl optionally substituted by alkyl, halo, or nitro, and for certain of these embodiments, R' is phenyl, p-bromophenyl, p-tolyl, 2- Nitrophenyl, or 4-nitrophenyl.

For certain embodiments, including any one of the above embodiments wherein R is present, R consists of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ Selected from the group. For certain of these embodiments, R is selected from the group consisting of hydroxy and bromo. For certain of these embodiments, R is at the 7- or 8-position. For certain of these embodiments, R is in the 7-position. Alternatively, for certain of these embodiments, R is in the 8-position.

For certain embodiments, including any one of the above embodiments wherein R is present, R a and is, except when R is selected from the group consisting of hydroxy, bromo Moro is R _a.

For certain embodiments, including any one of the above embodiments in which R _a is present, R _a is halogen, hydroxy, alkyl, alkenyl, trifluoromethyl, alkoxy, alkylthio, and -N (R _{9 2} ). For certain of these embodiments, R _a is selected from the group consisting of hydroxy and bromo. For certain of these embodiments, R _a is at the 7- or 8-position. For certain of these embodiments, R _a is in the 7-position. Alternatively, for certain of these embodiments, R _a is in the 8-position.

For certain embodiments, including any one of the preceding embodiments wherein R ₃ is present, R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ do. For certain of these embodiments, R ₃ is -ZR ₄ or -ZXR ₄ . For certain of these embodiments, R ₃ is -ZR ₄ . Alternatively, for certain of these embodiments, R ₃ is -ZXR ₄ . For certain of any of these embodiments, Z is -O-. For certain of these embodiments, R ₃ is methoxy, phenoxy, or benzyloxy. For certain of these embodiments, R ₃ is at the 7- or 8-position. For certain of these embodiments, R ₃ is in the 7-position. For certain of these embodiments, R ₃ is a benzyloxy group at the 7-position. Alternatively, for certain of these embodiments, R ₃ is in the 8-position.

Except for certain embodiments, including any one of the embodiments of the present R _3, R ₃ is -ZR _4, -ZXR _4, methoxy, phenoxy, or benzyloxy, and the case is, R ₃ Is R _3a .

For certain embodiments, including any one of the foregoing embodiments where R _3a is present, R _3a is -ZR _4a , -ZXR _4a , -ZXY _a -R _4a , -ZXY _a -XY _a -R _4a , and -ZXR _5a . For certain of these embodiments, R _3a is -ZR _4a or -ZXR _4a . For certain of these embodiments, R _3a is -ZR _4a . Alternatively, for certain of these embodiments, R _3a is -ZXR _4a . For certain of any of these embodiments, Z is -O-. For certain of these embodiments, R _3a is methoxy, phenoxy, or benzyloxy. For certain of these embodiments, R _3a is at the 7- or 8-position. For certain of these embodiments, R _3a is in the 7-position. For certain of these embodiments, R _3a is a benzyloxy group at the 7-position. Alternatively, for certain of these embodiments, R _3a is in the 8-position.

For certain embodiments, including any one of the above embodiments wherein R ₄ is present, R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, Heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, Alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen , Nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino , (Dialkylamino) alkyleneoxy, and oxo (in the case of alkyl, alkenyl, alkynyl, and heterocyclyl) may be substituted by one or more substituents independently selected from the group consisting of. For certain of these embodiments, R ₄ is alkyl optionally substituted by hydroxy or oxo. For certain of these embodiments, R ₄ is a group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,2-dimethyl-4-oxopentyl, and (1-hydroxycyclobutyl) methyl Is selected from. For certain of these embodiments, R ₄ is 2-methylpropyl or 2-hydroxy-2-methylpropyl. For certain of these embodiments, R ₄ is 2-methylpropyl.

For certain embodiments, R ₄ is, as well as any of the embodiments in the present -XYR _4, R ₄ is a C _{1 -4} alkyl. For certain of these embodiments, R ₄ is methyl.

For certain embodiments, including any one of the above embodiments wherein R _4a is present, R _4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, Heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, Alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, trifluoro Methoxy, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, di It may be substituted by one or more substituents independently selected from the group consisting of alkylamino, and (dialkylamino) alkyleneoxy. For certain of these embodiments, R _4a is alkyl optionally substituted by hydroxy. For certain of these embodiments, R _4a is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, and (1-hydroxycyclobutyl) methyl. For certain of these embodiments, R _4a is 2-methylpropyl or 2-hydroxy-2-methylpropyl. For certain of these embodiments, R _4a is 2-methylpropyl.

For certain embodiments, R _4a is, as well as any of the embodiments in the present -XYR _4a, R _4a is a C _{1 -4} alkyl. For certain of these embodiments, R _4a is methyl.

및

로 이루어진 군으로부터 선택된다. 이들 중 특정 실시양태에 대해, R₅는

이다. 이들 중 특정 실시양태에 대해, V'은 -NH-C(O)-이다. 이들 중 특정 실시양태에 대해, A는 -O-이다. 이들 중 특정 실시양태에 대해, a 및 b는 각각 2이다.For certain embodiments, including any one of the above embodiments wherein R ₅ is present, R ₅ is

And

It is selected from the group consisting of. For certain of these embodiments, R ₅ is

to be. For certain of these embodiments, V ′ is -NH-C (O)-. For certain of these embodiments, A is -O-. For certain of these embodiments, a and b are each 2.

For certain embodiments, including any one of the above embodiments in which R ₅ is present, R ₅ is R _5a .

로 이루어진 군으로부터 선택된다. 이들 중 특정 실시양태에 대해, R_5a는

이다. 이들 중 특정 실시양태에 대해, V'은 -NH-C(O)-이다. 이들 중 특정 실시양태에 대해, A는 -0-이다. 이들 중 특정 실시양태에 대해, a 및 b는 각각 2이다.For certain embodiments, including any one of the above embodiments in which R _5a is present, R _5a is

It is selected from the group consisting of. For certain of these embodiments, R _5a is

to be. For certain of these embodiments, V ′ is -NH-C (O)-. For certain of these embodiments, A is -0-. For certain of these embodiments, a and b are each 2.

For certain embodiments, R ₁₁ and R ₁₂ are independently C _{1 -4} alkyl or, or R ₁₁ and R ₁₂ is -O- together with the nitrogen atom to which they are attached, -N (C _{1 -4} alkyl) -, Or 5- or 6-membered ring optionally containing -S-. For certain embodiments, R ₁₁ and R ₁₂ are each methyl.

For certain embodiments, including any one of the above embodiments wherein X is present, X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein Alkylene, alkenylene, and alkynylene groups may be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene, and may be optionally interrupted by one or more -O- groups. For a specific embodiment of these state amounts, X is alkylene C _{2 -6.} For certain embodiments of these, X is alkylene C _{2 -4.}

,

,

,

, 및

로 이루어진 군으로부터 선택된다. 이들 중 특정 실시양태에 대해, Y는 -S(O)₂- 또는 -N(R₈)-Q-이다.For certain embodiments, including any one of the foregoing embodiments where Y is present, Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O) -O-, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-,- C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ ) -Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And

It is selected from the group consisting of. For certain of these embodiments, Y is -S (O) ₂ -or -N (R ₈ ) -Q-.

For certain embodiments, including any one of the foregoing embodiments wherein Y is present, Y is Y _a .

,

,

,

, 및

로 이루어진 군으로부터 선택된다. 이들 중 특정 실시양태에 대해, Y_a는 -S(O)₂- 또는 -N(R₈)-Q-이다.For certain embodiments, including any one of the above embodiments in which Y _a is present, Y _a is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ ) -, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-,

,

,

,

, And

It is selected from the group consisting of. For certain of these embodiments, Y _a is -S (O) ₂ -or -N (R ₈ ) -Q-.

As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix “alk-” include both straight and branched chains, and cyclic groups such as cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain 1 to 20 carbon atoms, for alkenyl groups 2 to 20 carbon atoms and for alkynyl groups 2 to 20 carbon atoms. In certain embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. The cyclic group may be monocyclic or polycyclic and preferably has 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, adamantyl, and substituted and unsubstituted bornyl, norbor Nil, and norbornenyl.

Unless specified otherwise, "alkylene", "alkenylene", and "alkynylene" refer to the divalent form of the "alkyl", "alkenyl", and "alkynyl" groups as defined above. The terms "alkylenyl", "alkenylenyl", and "alkynylenyl" are used when "alkylene", "alkenylene", and "alkynylene" are each substituted. For example, an arylalkylenyl group includes an alkylene moiety to which an aryl group is attached.

The term "haloalkyl" includes groups substituted by one or more halogen atoms, including perfluoro groups. This also includes the case of other groups that include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl and the like.

The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.

Unless otherwise indicated, the term “heteroatom” refers to the atom O, S, or N.

The term “heteroaryl” includes aromatic rings or ring systems containing at least one ring heteroatom (eg, O, S, N). In certain embodiments, the term “heteroaryl” includes rings or rings containing 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and N as heteroatoms System is included. Exemplary heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindoleyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thia Zolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, furinyl, Quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadizolyl, thiadiazolyl and the like.

The term “heterocyclyl” includes non-aromatic rings or ring systems containing at least one ring heteroatom (eg, O, S, N), and includes all of the saturated and partially unsaturated derivatives of the heteroaryl groups mentioned above. Included. In certain embodiments, the term "heterocyclyl" includes a ring containing 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and N as heteroatoms, or Ring systems are included. Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imida Zolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azpanyl), 1,4-oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxola Nil, aziridinyl, azetidinyl, dihydroisoquinolin- (1H) -yl, octahydroisoquinolin- (1H) -yl, dihydroquinolin- (2H) -yl, octahydroquinoline- (2H)- One, dihydro-1H-imidazolyl, 3-azabicyclo [3.2.2] non-3-yl and the like.

The term “heterocyclyl” includes bicyclic and tricyclic heterocyclic ring systems. Such ring systems include fused and / or bridged rings and spiro rings. Fused rings may also include saturated or partially saturated rings, aromatic rings, such as benzene rings. Spiro rings include two rings linked by one spiro atom and three rings linked by two spiro atoms.

When "heterocyclyl" contains a nitrogen atom, the point of attachment of the heterocyclyl group may be a nitrogen atom.

The terms "arylene", "heteroarylene", and "heterocyclylene" refer to the divalent forms of the "aryl", "heteroaryl", and "heterocyclyl" groups as defined above. The terms "arylenyl", "heteroarylenyl", and "heterocyclylenyl" are used when "arylene", "heteroarylene", and "heterocyclylene" are each substituted. For example, an alkylarylenyl group includes an arylene moiety to which an alkyl group is attached.

The term “fused 5- to 7-membered saturated ring” includes rings that are fully saturated except for the bond to which the ring is fused.

When one or more groups (or substituents or variables) are present in any of the formulas described herein, each group (or substituent or variable) is independently selected, whether explicitly stated or not. For example, when more than one R 'group is present, each R' group is independently selected. In another example, a group the formula _{0 (-C (O) -R 2} ) each of R _{2 2} is independently selected.

The present invention includes compounds described herein in any of their pharmaceutically acceptable forms, including isomers (eg, diastereomers and enantiomers), salts, solvates, polymorphs, prodrugs, and the like. In particular, when the compounds are optically active, the present invention clearly includes enantiomers of each compound as well as racemic mixtures of the enantiomers. The term "compound" is to be understood to include any or all such forms, whether explicitly or not (sometimes explicitly referring to "salt").

Preparation of the compound

More specific details of the reactions described herein are discussed in the context of the following schemes.

Certain embodiments of the invention are set forth below in Schemes I-IX. For a more detailed description of the individual reaction steps, see the Examples section below. Starting materials are generally available from commercial sources such as Aldrich Chemicals; Milwaukee, Wisconsin, USA, or methods well known to those skilled in the art (see, for example, Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.)]; Alan R. Katritsky, Otto Meth-Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations, v. 1-6 , Pergamon Press, Oxford, England, (1995); Barry M. Trost and Ian Fleming, Comprehensive Organic Synthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); or Beilsteins Handbuch der organischen Chemie, 4, Aufl.Ed.Springer-Verlag, Berlin, Germany], and supplements (which are also prepared by the methods generally described in the Wienstein online database). .

Although specific starting materials and reagents are shown in the schemes and discussed below, they may be replaced with other starting materials and reagents known to those skilled in the art to provide a variety of derivatives and / or reaction conditions. In addition, many of the methods described below may be further described in light of the present disclosure using conventional methods well known to those skilled in the art.

In carrying out the process of the invention, it may sometimes be necessary to protect certain functional groups while reacting other functional groups of the intermediate. The need for such protection will depend on the nature of the particular functional group and the conditions of the reaction step. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc). Suitable hydroxy protecting groups include acetyl and silyl groups such as tert-butyl dimethylsilyl group. For a general description of protecting groups and their use, refer to the literature [Greene TW and Wuts PGM, Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons, New York, USA, 1999].

Conventional methods and techniques of separation and purification can be used to isolate the compounds set forth in the following schemes. Such techniques include, for example, all types of chromatography (high performance liquid chromatography (HPLC), column chromatography using conventional absorbents such as silica gel, and thin layer chromatography), recrystallization, and fractionation (ie liquid-liquid). Extraction techniques can be included.

The process of the present invention is shown in Scheme I, wherein R _A , R _B , R ₁ , R ₂ , E, and L are as defined above. In step (1) or (1a) of Scheme I, 3-nitropyridine, 3-nitroquinoline, or 3-nitronaphthyridine of formula (V) or (II) is selected from 3-aminopyridine, 3-aminoquinoline, Or 3-aminonaphthyridine, respectively. Reduction can be carried out by a number of conventional methods. For example, the reaction can be carried out by hydrogenation with heterogeneous hydrogenation catalysts such as platinum on carbon or Raney nickel. Hydrogenation can conveniently be carried out in a suitable solvent such as N, N-dimethylformamide (DMF) in a Parr apparatus at room temperature. Reduction can also be carried out using nickel boride prepared from sodium borohydride and nickel (II) chloride in situ. Nickel boride reduction is added to a mixture of an excess of sodium borohydride and a catalytic or stoichiometric amount of nickel (II) chloride in methanol in a suitable solvent or solvent mixture, such as dichloromethane / methanol. By doing so conveniently. The reaction can be carried out at room temperature. Alternatively, the reduction may be carried out using mono- or bi-phase sodium hyposulfite reduction. Sodium hyposulfite reduction is described by Park, KK; Oh, CH; and Joung, WK; Tetrahedron Lett., 34, pp. 7445-7446 (1993), using sodium hyposulfite to a compound of formula V or II in a mixture of dichloromethane and water at ambient temperature potassium carbonate and ethyl viologen dibromide, ethyl viologen diiodide Or in the presence of 1,1'-di-n-octyl-4,4'-bipyridinium dibromide.

Numerous compounds of formulas V and II are known and else can be prepared by known methods. For quinolines and [1,5] naphthyridine of Formulas V and II, wherein E is hydrogen and L is chloro, U.S. Pat. Nos. 4,689,338 to Gerster and 6,194,425 to Gerster et al. See references. Quinoline, tetrahydroquinoline, and pyridine of formula II wherein E and L are each chloro or -0-S (O) ₂ -R 'can be prepared from compounds of formula V wherein E is hydroxy (e.g., U.S. Patent 4,988,815 (Andre et al.), 5,395,937 (Nikolaides et al.), 5,352,784 (Nikolaides et al.), 5,446,153 (Lindstrom et al.), And 6,743,920 (See Lindstrom et al. And references cited therein). For quinoline and naphthyridine of Formula V or II, wherein E is part of the tetrazolo ring and L is chloro or -0-S (O) ₂ -R ', U.S. Pat.Nos. 6,194,425 (Gerster et al.) And See Gerster et al. And the references cited therein. Compounds of formula II wherein E and / or L are phenoxy can be prepared from the compounds of formula II wherein E and / or L is chloro using the method described in 6,743,920 (Lindstrom et al.). Compounds of formula II wherein E is -N (Bn) _{2 are represented} by the compounds of formula II wherein E is -0-S (O) ₂ -R ', 5,395,937 (Nikolaides et al.) And 5,352,784 (Nikolaides et al. It can manufacture according to the method as described in.).

Several compounds of formula VI, wherein E is hydrogen, are known compounds, including unsubstituted and substituted pyridine, quinoline, and naphthyridine, of each isomeric variant. See, eg, US Pat. No. 6,110,929 (Gerster et al.) And the references cited therein. In addition, certain compounds of formula III are known. For example, 3-amino-4-chloroquinoline, 3-amino-4,5-dichloroquinoline, and 3-amino-4,7-dichloroquinoline are described in Surrey et al., Journal of the American Chemical Society, 73, pp. 2413-2416 (1951).

In step (2) or (3a) of Scheme I, 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI or III is reacted with a carboxylic acid or its equivalent to an amide of formula VII or IV. -Each of the substituted compounds is provided. Suitable equivalents for carboxylic acids include acid anhydrides and acid halides. The choice of carboxylic acid equivalent is determined by the preferred substituents at R ₂ . For example, the use of butyryl chloride provides compounds wherein R ₂ is a propyl group; Use of ethoxyacetyl chloride provides a compound wherein R ₂ is an ethoxymethyl group. The reaction comprises the reaction of an acid halide of formula R ₂ C (O) Cl or R ₂ C (O) Br with a compound of formula VI or III, optionally in a suitable solvent such as dichloromethane, acetonitrile, or 1,2-dichloroethane. It can be conveniently carried out in combination in the presence of a tertiary amine such as triethylamine, pyridine, or 4-dimethylaminopyridine (DMAP). The reaction can be carried out at reduced temperature, for example 0 ° C., room temperature, or at elevated temperatures such as 40 ° C. to 90 ° C. For compounds wherein R ₂ is hydrogen, compounds of formula VI or III may be reacted with formylating agents such as diethoxymethyl acetate or acetic anhydride. Certain compounds of formula VII are known (see, eg, US Pat. No. 6,110,929 (Gerster et al)).

In step (3) of Scheme I, the hydroxy group in the compound of formula VII is converted to a leaving group using a conventional activation method to provide a compound of formula IV. For example, the conversion of the hydroxy group to the chloro group can be conveniently carried out by combining the compound of formula VII with phosphorus oxychloride (III). The chlorination reaction is carried out without solvent or in a suitable solvent such as N, N-dimethylformamide (DMF), dichloromethane, acetonitrile, 1-methyl-2-pyrrolidinone (NMP), and 1,2-dichloroethane can do. The reaction can be carried out at an elevated temperature on the order of room temperature or reflux temperature, for example from 25 ° C to 120 ° C. Other examples of chlorinating agents include, for example, thionyl chloride, phosgene, oxalyl chloride, and phosphorus pentachloride. Other halogenating agents include phosphorus (III) oxybromide, phosphorous bromide, diphenylphosphine chloride, and triphenylphosphine in the presence of bromine. In the compounds of formula (VII) the hydroxy groups can also be converted to sulfonate esters, for example by reacting with sulfonyl halides or sulfonic anhydrides. Suitable sulfonating agents include methanesulfonyl chloride, methanesulphonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulphonic anhydride, N-phenylbis (trifluoromethanesulfonimide), benzenesulfonyl chloride, benzenesulfonic anhydride , p-bromobenzenesulfonyl chloride, p-bromobenzenesulphonic anhydride, p-toluenesulfonyl chloride, p-toluenesulphonic anhydride, 2-nitrobenzenesulfonyl chloride and 4-nitrobenzenesulfonyl chloride. The reaction with the sulfonating agent is typically carried out in the presence of a base. Preferably, the base is a tertiary amine such as triethylamine. The reaction can be carried out in a suitable solvent such as dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran (THF), DMF, and NMP. The reaction can also be carried out in pyridine which can be used as both base and solvent for the reaction. The reaction can be carried out at room temperature or elevated temperature, such as the reflux temperature of the solvent. Preferably, reaction temperature is about room temperature to 90 degrees C or less. These methods described for step (3) of Scheme I also provide 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of Formula VI, as shown in step (2a) of Scheme I, It can be used to convert into a compound.

In step (4) of Scheme I, the amide of formula IV is reacted with an amine of formula R ₁ NH ₂ , or a suitable salt thereof, to produce the 1H-imidazo compound of formula I. The reaction can be carried out without solvent, at elevated temperatures, such as the temperature required to melt the mixture. The reaction can also be carried out at elevated temperature in a suitable solvent. Suitable solvents include alcohols such as methanol, ethanol, trifluoroethanol, isopropanol, and tert-butanol; water; Acetonitrile; NMP; And toluene. Preferred solvents include trifluoroethanol, isopropanol, and tert-butanol. Preferably, reaction temperature is 80 degreeC or more and 200 degrees C or less. More preferably, reaction temperature is 180 degrees C or less. More preferably, reaction temperature is 110 degreeC-165 degreeC. Optionally, bases can be used in the reaction. Suitable bases include triethylamine. Optionally, a catalyst such as pyridine hydrochloride, pyridinium p-toluenesulfonate, or p-toluenesulfonic acid can be added. For certain amines of the formula R ₁ NH ₂ under certain conditions, an acyclic 3-amido-4-amino intermediate can be isolated. The intermediate can then be cyclized in a subsequent step by heating in a solvent such as toluene, optionally in the presence of a catalyst such as pyridine hydrochloride or pyridinium p-toluenesulfonate. Cyclization can be performed at elevated temperatures, such as the reflux temperature of the solvent.

Many primary amines of formula R ₁ NH ₂ , or salts thereof, suitable for this reaction are commercially available; In addition, it can manufacture by a well-known method. See, for example, US Pat. Nos. 6,451,810 (Coleman et al.), 6,660,747 (Crooks et al.), 6,683,088 (Crooks et al.), And 6,656,938 (Crooks et al.); US Patent Application Publication No. 2004/0147543 (Hays et al.); And the method of WO2005 / 051317 (Krepski et al.).

Certain amines of formula R ₁ NH ₂ can be prepared according to the following procedure. For certain embodiments, R ₁ is a 1-hydroxycycloalkylmethyl group. Corresponding amines of formula R ₁ NH ₂ are combined with an excess of nitromethane with a cyclic ketone such as cyclopentanone or cyclobutanone in the presence of a catalytic amount of base such as sodium ethoxide or sodium hydroxide in a suitable solvent such as ethanol or methanol. Can be combined and prepared to reduce the resulting nitromethyl-substituted compounds using conventional heterogeneous hydrogenation conditions. Hydrogenation is typically carried out in a suitable solvent such as ethanol in the presence of a catalyst such as palladium hydroxide on carbon, palladium on carbon, or Raney nickel. Both reaction and reduction with nitromethane can be carried out at room temperature. A wide range of cyclic ketones can be obtained from commercial sources and else can be synthesized using known synthetic methods.

Compounds of formula (I) can be converted to compounds of formula (X) using a variety of methods depending on the identity of E. Examples of such methods are shown in Schemes II-V.

For certain embodiments, amination of a compound of Formula I ₁ is shown in Scheme II, wherein E ₁ is halogen, phenoxy, or —0-S (O) ₂ —R ′, RA, RB, R ₁ , R2 is as defined above. Step (1) of Scheme II can be used to convert a compound of formula (I-4), wherein E is hydroxy, to a compound of formula (I1). Any one of the methods described in Scheme I step (3) and step (2a) can be used. The amination in step (2) of Scheme II can be conveniently carried out by heating together a compound of formula I ₁ and a solution of ammonia in a suitable solvent such as methanol. Amination may also be carried out by using ammonium acetate or ammonium hydroxide in combination with a compound of formula I ₁ and heating. Amination is preferably carried out at a temperature of at least 100 ° C, preferably at least 125 ° C, more preferably at least 140 ° C. The reaction is preferably carried out at a temperature of 200 ° C. or lower, more preferably 170 ° C. or lower.

Alternatively, the compound of Formula I ₁ may be converted to the compound of Formula X in two steps as shown in Scheme III, wherein R _A , R _B , R ₁ , R ₂ , E ₁ , and Bn are as defined above. As it is. Step (1) of Scheme III can be used to replace the E ₁ group in the compound of Formula I _{1 with} an amine of Formula HN (Bn) ₂ to provide a compound of Formula I-6. The replacement can be conveniently carried out by combining the amine of formula HN (Bn) ₂ with the compound of formula I ₁ in the presence of a base such as triethylamine in a suitable solvent such as toluene or xylene and heating at an elevated temperature such as the reflux temperature of the solvent. Can be. In step (2) of Scheme III, the protecting group is removed from the 4-amine of the compound of formula I-6 to provide a compound of formula X. For certain embodiments, deprotection can be conveniently performed in a solvent such as ethanol using a heterogeneous catalyst suitable such as palladium on carbon under hydrolysis conditions on a Parr apparatus. Alternatively, when Bn is p-methoxybenzyl, step (2) can be carried out by combining trifluoroacetic acid with a compound of formula (I-6) and stirring at room temperature or heating at elevated temperature, such as from 50 ° C. to 70 ° C. have.

For certain embodiments, compounds of Formula (I), wherein E is hydrogen, can be converted to compounds of Formula (X ₂₎ by oxidation and amination as shown in Scheme IV, wherein R _A2 and R _B2 together are a fused benzene ring or Forming a fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, substituted by one R group and one R ₃ group, R ₁ and R ₂ are as defined above. In step (1) of Scheme IV, the compound of formula I-2 ₂ is oxidized to 5N-oxide of formula XX ₂ using conventional oxidizing agents capable of forming N-oxides. The reaction is conveniently carried out by combining 3-chloroperoxybenzoic acid with a compound of formula I-2 ₂ in a suitable solvent such as dichloromethane or chloroform. The reaction can be carried out at room temperature. Alternatively, other peracids such as peracetic acid can be used as oxidant. The reaction with peracetic acid can be carried out at an elevated temperature such as 50 ° C. to 60 ° C. in a suitable solvent such as ethanol. The 5N-oxide of formula XX ₂ is then aminated in step (2) of scheme IV to provide a compound of formula X ₂ . Amination can be carried out by converting the 5N-oxide into an ester to activate and then reacting the ester with an amination agent. Suitable activators include alkyl- or arylsulfonyl chlorides such as benzenesulfonyl chloride, methanesulfonyl chloride, or p-toluenesulfonyl chloride. Suitable amination agents include, for example, ammonia in the form of ammonium hydroxide, and ammonium salts such as ammonium carbonate, ammonium bicarbonate, and ammonium phosphate. The reaction is conveniently carried out by adding p-toluenesulfonyl chloride to a mixture of ammonium hydroxide and a solution of 5N-oxide in a suitable solvent such as dichloromethane or chloroform. The reaction can be carried out at room temperature. The oxidation and amination step can be carried out in a one-pot procedure without isolating the 5N-oxide of formula XX ₂ . Alternatively, the 5N-oxide is treated in step (2) with isocyanate having an isocyanato group bound to a hydrolytically active functional group and subsequent hydrolysis of the resulting intermediate to give a compound of formula X ₂ can do. The reaction can be conveniently carried out in the following two steps, in step (i) a solution of 5N-oxides in an isocyanate such as trichloroacetyl isocyanate and a solvent such as dichloromethane is combined and stirred at room temperature to isolate the amide intermediate To provide. In step (ii), a solution of the intermediate in methanol can be treated with a base such as sodium methoxide at room temperature.

Alternatively, the 5N-oxide of formula XX can be converted to a compound of formula I _{1 wherein} E ₁ is chloro using one of the methods described in step (3) of Scheme I. The resulting 4-chloro compound can then be aminated according to the method described in Scheme II.

For embodiments wherein E combines with the pyridine nitrogen atom of the compound of formula I to form a ring with a fused tetrazolo ring, the tetrazolo ring can be removed to form a compound of formula X as shown in Scheme V, wherein R _A , R _B , R ₁ and R ₂ are as defined above and Ph is phenyl. In step (1) of Scheme V, the compound of formula I-1 is combined with triphenylphosphine to form an N-triphenylphosphinyl intermediate of formula XXI. The reaction with triphenylphosphine can be carried out in a suitable solvent such as toluene or 1,2-dichlorobenzene under heating of nitrogen, for example at reflux temperature.

In step (2) of Scheme V, the N-triphenylphosphinyl intermediate of Formula XXI is hydrolyzed to provide a compound of Formula X. Hydrolysis can be carried out by heating in the presence of an acid such as trifluoroacetic acid, acetic acid, or hydrochloric acid in a general method well known to those skilled in the art, for example in lower alkanol or alkanol / water solutions. Compounds of formula (X) can also be obtained via alternative routes as set forth in step (1a) of Scheme V. In step (1a), the tetrazolo ring is removed reductively from the compound of formula (I-1) to provide a compound of formula (X). The reaction can be carried out by reacting the compound of formula I-1 with hydrogen in the presence of a catalyst and an acid. Hydrogenation can conveniently be carried out on a Parr apparatus at ambient temperature with a suitable catalyst such as platinum (IV) and a suitable acid such as trifluoroacetic acid or hydrochloric acid. The reaction can optionally be carried out in the presence of a solvent such as ethanol. When using step (1a), the compound of formula (I-1) in which R _A and R _B together form a fused benzene ring or a fused pyridine ring is a 5-membered fused compound in which R _A and R _B optionally contain one nitrogen atom together. To a compound of formula (X) which forms a seven-membered saturated ring. Those skilled in the art will understand that other groups that are likely to be reduced, such as alkenyl, alkynyl, and aryl groups, will be reduced in step (1a).

For certain embodiments, compounds of Formula (X _b ) may be reduced according to Scheme VI, wherein R _A3 and R _B3 together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted Or substituted by one R _b group, substituted by one R _3b group, or substituted by one R _b group and one R _3b group; R _A4 and R _B4 together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R _b groups; R _1b , R _2b , R _3b , and R _b are subgroups of R ₁ , R ₂ , R ₃ , and R as defined above, which are substituents that will be recognized by those skilled in the art as prone to reduction under acidic hydrogenation conditions of the reaction. do not include. These easy-reducing groups include, for example, alkenyl, alkynyl, and groups containing aryl groups and nitro substituents.

As shown in Scheme VI, 1H-imidazo [4,5-c] quinolin-4-amine or 1H-imidazo [4,5-c] [1,5] naphthyridin-4-amine of formula X _b Can be reduced to 6,7,8,9-tetrahydroquinoline or tetrahydronaphthyridine of formula X _c . Compounds of formula (X _b ) may be prepared according to the methods described in Schemes II, III, IV, or V. The reaction is conveniently carried out by adding platinum (IV) oxide to a solution of the compound of formula X _b in trifluoroacetic acid under heterogeneous hydrogenation conditions and placing the reaction under hydrogen pressure. The reaction can be carried out at ambient temperature on a Parr apparatus.

, 또는

의 보호된 디아민은 상업적으로 입수가능하거나, 또는 공지된 방법에 의해 제조할 수 있다 (예를 들어, 미국 특허 제6,660,747호 (Crooks et al.), 동 제6,683,088호 (Crooks et al.), 및 동 제6,656,938호 (Crooks et al.) 및 문헌 [Carceller, E. et al., J. Med. Chem., 39, pp.487-493 (1996)] 참조). 보호기는 반응식 I의 단계 (4)에서 제시된 고리화 단계 후에, 또는 반응식 II 내지 VI에서 제시된 단계 후에 제거되어, 예를 들어 R₁기 상의 아미노 치환기를 드러낼 수 있다. 이러한 방식으로 도입된 아미노기는 화학식 R₄C(O)Cl의 산 클로라이드, 화학식 R₄S(O)₂Cl의 술포닐 클로라이드, 화학식 (R₄S(O)₂)₂O의 술폰산 무수물, 또는 화학식 R₄N=C=O의 이소시아네이트와 반응시켜, R₁은 -X-N(R₈)-Q-R₄,

, 또는

이고, 여기서 X, R₄, R₇, R₈, 및 R₁₀은 상기 정의된 바와 같고, Q는 -C(O)-, -SO₂-, 또는 -C(O)-NH-인 화학식 X의 화합물을 제공할 수 있다. 다수의 산 클로라이드, 술포닐 클로라이드, 술폰산 무수물, 및 이소시아네이트는 상업적으로 입수가능하며; 그 외에는 공지된 합성 방법을 이용하여 용이하게 제조할 수 있다. 반응은 산 클로라이드, 술포닐 클로라이드, 술폰산 무수물, 또는 이소시아네이트, 및 적합한 용매, 예컨대 디클로로메탄 중 아미노-치환된 화합물, 및 염기, 예컨대 트리에틸아민의 용액을 합하여 편리하게 수행할 수 있다. 반응은 실온에서 수행할 수 있다.For certain embodiments, the compounds shown in Schemes I-VI can be further prepared using conventional synthetic methods. The amines of formula R ₁ NH ₂ used in step (4) of Scheme I may contain protected functional groups such as tert-butoxycarbonyl-protected amino groups. For example, the formula Boc-N (R ₈ ) -X-NH ₂ ,

, or

Protected diamines are commercially available or can be prepared by known methods (eg, US Pat. No. 6,660,747 (Crooks et al.), 6,683,088 (Crooks et al.), And 6,656,938 (Crooks et al.) And Carceller, E. et al., J. Med. Chem., 39, pp. 487-493 (1996)). The protecting group can be removed after the cyclization step as shown in step (4) of Scheme I or after the steps as shown in Schemes II to VI to reveal, for example, amino substituents on the R ₁ group. The amino groups introduced in this way are acid chlorides of formula R ₄ C (O) Cl, sulfonyl chlorides of formula R ₄ S (O) ₂ Cl, sulfonic anhydrides of formula (R ₄ S (O) ₂ ) ₂ O, or By reacting with an isocyanate of the formula R ₄ N═C═O, R ₁ is —XN (R ₈ ) —QR ₄ ,

, or

Wherein X, R ₄ , R ₇ , R ₈ , and R ₁₀ are as defined above and Q is -C (O)-, -SO _2- , or -C (O) -NH- The compound of can be provided. Many acid chlorides, sulfonyl chlorides, sulfonic anhydrides, and isocyanates are commercially available; In addition, it can be manufactured easily using a well-known synthetic method. The reaction can be conveniently carried out by combining acid chloride, sulfonyl chloride, sulfonic anhydride, or isocyanate, and a solution of an amino-substituted compound in a suitable solvent such as dichloromethane, and a base such as triethylamine. The reaction can be carried out at room temperature.

Amines of formula R ₁ NH ₂ may also contain other protected functional groups, such as ketal-protected ketones. For example, 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propylamine prepared in Example 22 of WO2005 / 051317 (Krepski et al.). Can be used in step (4) of Scheme I. The ketal protecting group can then be removed by conventional methods to provide compounds of formula (I) or (X) wherein R ₁ is 2,2-dimethyl-4-oxopentyl.

The amino alcohols of formula H ₂ NX-OH can be used in step (4) of Scheme I, wherein the hydroxy functionality is described in US Pat. No. 6,664,264 (Dellaria et al.) And WO 2005/066169 ( Bonk and Dellaria, WO 2005/018551 (Kshirsagar et al.), WO 2005/018556 (Kshirsagar et al.), And WO 2005/051324 (Krepski et al.), Respectively. and, -XS (O) R ₁ in positions _{0-2 -R 4, -XS (O)} 2 -N (R 8) -R 4, -XON (R 8) -QR 4, -XON = C (R ₄ ) -R ₄ , -X-CH (-N (-OR ₈ ) -QR ₄ ) -R ₄ groups can be converted to compounds of formula (I) or (X).

The amine used in step (1) may be tert-butyl carbazate and the resulting compound of formula (I) or subsequently converted compound of formula (X) wherein R ₁ is a Boc-protected amino group is deprotected to give 1- Amino compounds or salts thereof (eg hydrochloride salts) may be provided. Deprotection can be carried out by heating a solution of a compound of formula (I) or (X) in ethanol hydrogen chloride at reflux temperature. The resulting compounds of formula (I) or (X), wherein R ₁ is an amino group, can be treated with ketones, aldehydes, or their corresponding ketals or acetals under acidic conditions. For example, the ketone may be acid, such as pyridinium p-toluene sulfonate or acetic acid, or acid resin, eg in a solution of the hydrochloride salt of a compound of formula I or X wherein R ₁ is an amino group in a suitable solvent such as isopropanol or For example, it can be added in the presence of DOWEX W50-X1 acid resin. The reaction can be carried out at elevated temperature. The resulting amine can be reduced to provide a compound of formula I or X wherein R ₁ is -N (R ₁ ′) -QR ₄ , wherein Q is a bond. The reduction can be carried out with sodium borohydride in a suitable solvent, for example methanol, at room temperature. tert-butyl hydrazinecarboxylate was also manipulated in a subsequent step using the method of US Patent Application Publication No. 2005/0054640, wherein R ₁ is —N (R ₁ ′) —QR ₄ , —N (R ₁ ′). It is possible to provide compounds of formula (I) or (X) which are -X ₁ -Y ₁ -R ₄ , or -N (R ₁ ′) -X ₁ -R _5b .

Other variations can be made at the R ₁ position. For example, U.S. Pat. No. 5,389,640 (Gerster et al.), 6,331,539 (Crooks et al), 6,451,810 (Coleman et al.), 6,541,485 (Crooks et al.), 6,660,747 (Crooks et al.), 6,670,372 (Charles et al.), 6,683,088 (Crooks et al.), 6,656,938 (Crooks et al.), 6,664,264 (Dellaria et al. ., 6,677,349 (Griesgraber), and 6,664,260 (Charles et al.).

For certain embodiments, for example, when the carboxylic acid equivalent used in step (2) or (3a) of Scheme I contains a protected or unprotected hydroxy group or a protected amino group, a compound of formula (I) or (X) Synthetic modifications may be made at the R ₂ position of. Certain carboxylic acid equivalents of this type are commercially available; Otherwise, it can manufacture by a well-known synthetic method. Protected hydroxy or amino groups formed at the R ₂ position can be deprotected by various methods well known to those skilled in the art. For example, a hydroxyalkylenyl group is conveniently introduced at the R ₂ position by dealkylation of a methoxy- or ethoxyalkylenyl group, which is carried out in step (2) or (3a) of Scheme I in It can be formed by using a oxy-substituted carboxylic acid equivalent. Dealkylation can be carried out by treating a compound of formula (I) or formula (X), wherein R ₂ is an alkoxyalkylenyl group, with boron tribromide in a suitable solvent such as dichloromethane at temperatures below ambient, such as 0 ° C. The resulting hydroxy group is then oxidized to an aldehyde or carboxylic acid, or converted to a leaving group, such as by converting to a chloro group using thionyl chloride, or trifluoromethanesulfonate using trifluoromethanesulfonic anhydride Can be converted into groups. The resulting leaving group can then be replaced by various nucleophiles. Sodium azide can be used as a nucleophile to form azide groups that can subsequently be reduced to amino groups using heterogeneous hydrogenation conditions. The amino group at the R ₂ position can be converted to an amide, sulfonamide, sulfamide, or urea using conventional methods. Leaving groups at R ₂ , such as chloro or trifluoromethanesulfonate groups, may also be replaced with secondary amines, substituted phenols, or mercaptans in the presence of a base such as potassium carbonate. For this example, and other methods used to form various groups at the R ₂ position, see US Pat. No. 5,389,640 to Gerster et al. These synthetic modifications can be carried out as the last step of the synthesis, or conveniently before the steps shown in Schemes II-VI.

1H-imidazo [4,5-c] quinolines of Formulas II and V, wherein the quinoline ring is substituted by a bromo, benzyloxy, or methoxy substituent, and E is hydrogen, are known or US Patent Application Publications It may be prepared according to the method described in 2004/0147543 (Hays et al.) And International Publication WO2005 / 020999 (Lindstrom et al.). These compounds can be applied to the method of Scheme I to give 1H-imidazo [4,5-c] quinoline of Formula I-2 ₂ , which can then be oxidized and aminated according to the method of Scheme IV. Subsequently, the compound in which the quinoline ring is substituted by a benzyloxy or methoxy group can be converted to the hydroxy-substituted 1H-imidazo [4,5-c] quinolin-4-amine of formula XXII shown below in Scheme VII. . Demethylation of the methoxy-substituted compound can be performed with boron tribromide as described in the previous paragraph. Alternatively, demethylation can be carried out by heating the methoxy-substituted compound with anhydrous pyridinium chloride at elevated temperature, such as 210 ° C. Removal of the benzyloxy group can be carried out as described in WO2005 / 020999 (Lindstrom et al.).

Then, 1H- imidazo [4,5-c] quinolin-4-amine Preparation of further synthesis may be carried out as shown in Scheme VII, wherein R _3c is _{-R 4, -XR 4, -XYR 4} , -XYXYR ₄ , or -XR ₅ ; R _3d is —OR ₄ , —OXR ₄ , —OXYR ₄ , —OXYXYR ₄ , or —OXR ₅ ; R _d is selected from the group consisting of halogen, alkyl, alkenyl, trifluoromethyl, and dialkylamino; n is 0 or 1; R ₁ and R ₂ are as defined above. In step (1) of Scheme VII, the hydroxy group of the 1H-imidazo [4,5-c] quinolin-4-amine of formula XXII is subjected to any one of the methods described in step (2a) or (3) Thus activated by conversion to a trifluoromethanesulfonate (triplate) group to give a compound of formula XXIII.

Step (2) of Scheme VII uses known palladium catalyzed coupling reactions such as Suzuki coupling, Heck reaction, Still coupling, and Sonogashira coupling, It can be carried out according to any of the methods described in US Patent Application Publication No. 2004/0147543 (Hays et al.) To provide compounds of formula XXIV. Compounds in which a bromo substituent is used in place of the triflate group in the compound of formula (XXIII) may alternatively be used in this modification. Suzuki coupling is performed with aryl or vinyl boronic acid, anhydrides thereof, or boronic acid esters. Heck reaction is carried out with vinyl-substituted compounds. Sonogashira and still coupling reactions can be carried out with alkyne, and any unsaturated compounds produced by these couplings can carry out the reduction of alkenylene or alkynylene groups.

In step (1a) of Scheme VII, the hydroxy-substituted 1H-imidazo [4,5-c] quinolin-4-amine of formula (XXII) is prepared using a Williamson-type ether synthesis Switch to The methods described in WO2005 / 020999 (Lindstrom et al.) And WO2005 / 032484 (Lindstrom et al.) Can be used.

For certain embodiments, the methods of the present invention are shown in Scheme VIII, wherein R _A , R _B , R ₁ , R ₁₁ , R ₁₂ , E, and L are as defined above. In step (1) of Scheme VIII, 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI is converted to imidoformamide of formula VIII. The reaction is carried out by reaction of 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI or a suitable salt thereof in the presence of formamide of formula HC (O) -N (R1 i) Ri2 (3 Or in combination with the halogenating or sulfonating agents described in (2a). Several formamides of the formula HC (O) -N (R ₁₁ ) R ₁₂ are commercially available, for example DMF, N, N-diethylformamide, and 1-formylpiperidine. Other formamides of this formula may be prepared by known methods, for example amines may be prepared in a suitable solvent such as THF, acetone, acetonitrile, ethyl acetate, tert-butyl methyl ether, DMF, NMP, dichloromethane, toluene It can be prepared by combining with a mixture of formic acid and acetic anhydride in, xylene, methanol, and ethanol. The reaction can be carried out at room temperature, at a temperature below room temperature of about 0 ° C. to room temperature, or at an elevated temperature on the reflux temperature of the solvent. Step (1) of Scheme VIII may be carried out in a solvent such as dichloromethane, 1,2-dichloroethane, acetonitrile, THF, toluene, and NMP, or in certain embodiments, the reaction may be carried out in excess DMF. Can be. The reaction can be carried out at room temperature, below room temperature, such as at least 0 ° C., or at elevated temperatures such as below the reflux temperature of the solvent. For certain embodiments, the reaction temperature is 40 ° C. or less. For certain embodiments, step (1) of Scheme VIII may be carried out by combining the compound of formula VI in phosphorus oxychloride with excess DMF at room temperature or elevated temperature, such as 150 ° C. or less. For certain embodiments, DMF can be used as the solvent. For certain embodiments, the reaction temperature is 15 ° C to 30 ° C.

For certain embodiments, the conversion of the 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of Formula VI to imidoformamide of Formula VIII is performed in two steps, such as steps (1a) and (2a) in Scheme VIII. ), Or (1b) and (2b). Steps (1b) and (2a) can be carried out in a solvent other than DMF according to the method described in step (3) or (2a) of Scheme I. Steps (1a) and (2b) can be performed as described in step (1) of Scheme VIII, except in the absence of halogenating or sulfonating agents.

In step (3) of Scheme VIII, imidoformamide of formula VIII is reacted with an amine of formula R ₁ NH ₂ , or a suitable salt thereof, to provide a 1H-imidazo compound of formula IH. The reaction can be carried out without solvent, at elevated temperatures, such as the temperature required to melt the mixture. The reaction can also be carried out at room temperature or at elevated temperature in a suitable solvent. Suitable solvents include alcohols such as methanol, ethanol, trifluoroethanol, isopropanol, and tert-butanol; water; Acetonitrile; NMP; Toluene, and tetrahydrofuran. Preferred solvents include trifluoroethanol, isopropanol, tert-butanol, and acetonitrile. Preferably, reaction temperature is 250 degrees C or less. The reaction can be carried out at a temperature below 200 ° C. or at a temperature below 180 ° C. Optionally, bases can be used in the reaction. Suitable bases include triethylamine. Optionally, a catalyst such as pyridine hydrochloride, pyridinium p-toluenesulfonate, or p-toluenesulfonic acid can be added.

가 반응식 VIII의 단계 (3) 동안 형성될 수 있다. 특정 실시양태에 대해, 화학식 XI의 중간체를 반응 혼합물로부터 단리한다. 이어서 중간체는 후속적인 단계에서 고리화할 수 있다. 고리화는 임의로 용매, 예컨대 이전 단락에 기재된 것 중에서 임의로 촉매, 예컨대 피리딘 히드로클로라이드, 피리디늄 p-톨루엔술포네이트, 또는 p-톨루엔술폰산의 존재 하에 가열함으로써 수행할 수 있다. 바람직하게는, 고리화 반응 온도는 250℃ 이하이다. 고리화는 200℃ 이하의 온도 또는 180℃ 이하의 온도에서 수행할 수 있다.Under certain conditions, the imidoformamide intermediate of formula (XI)

Can be formed during step (3) of Scheme VIII. For certain embodiments, the intermediate of Formula (XI) is isolated from the reaction mixture. The intermediate can then be cyclized in subsequent steps. Cyclization can optionally be performed by heating in the presence of a solvent, such as those described in the previous paragraphs, optionally in the presence of a catalyst such as pyridine hydrochloride, pyridinium p-toluenesulfonate, or p-toluenesulfonic acid. Preferably, cyclization reaction temperature is 250 degrees C or less. Cyclization can be carried out at a temperature below 200 ° C. or at a temperature below 180 ° C.

For certain embodiments, steps (1) and (3) of Scheme VIII are performed in a one-pot procedure without isolating the compound of Formula VIII. The process can be carried out by adding the amine of formula R ₁ NH ₂ , or a suitable salt thereof, directly to the reaction mixture from step (1) of Scheme VIII. Optionally, the reaction mixture can be filtered before the addition of the amine of formula R ₁ NH ₂ . The resulting mixture can then be subjected to the conditions of step (3) to give the compound of formula IH.

For certain embodiments, the methods of the present invention are shown in Scheme IX, wherein R _A , R _B , R ₁ , E, and L are as defined above. In step (1) of Scheme IX, 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI is converted to imidoformamide of formula XI. Step (1) of Scheme IX is carried out using formamide of formula HC (O) -NHR ₁ instead of formula HC (O) -N (R ₁₁ ) R ₁₂ under the conditions described for step (1) of scheme VIII. Can be done. Certain formamides of the formula HC (O) -NHR ₁ are commercially available. Others can be prepared by known methods, for example the amine of formula R ₁ NH ₂ is described in step (1) of Scheme VIII in connection with the preparation of HC (O) —N (R ₁₁ ) R ₁₂ . Any solvent and conditions may be used to combine with a mixture of formic acid and acetic anhydride. Alternatively, the amine of formula R ₁ NH ₂ may be combined with other formylating agents such as methyl formate, formamide, and chloroform under conditions known to those skilled in the art in the presence of sodium hydroxide (eg, see J. Org.Chem., 23, p. 1032 (1958), J. Am. Chem. Soc. 78, p. 2467 (1956), J. Chem. Soc, p. 858 (1957), J. Am. Chem. Soc. 74, p. 5619 (1952), and Tetrahedron Lett., 7, p. 5 (1959)). The compound of formula (XI) can be isolated from the reaction mixture before step (2) of Scheme IX, or steps (1) and (2) can be carried out without isolating the compound of formula (XI).

When isolating imidoformamide of formula (XI), the compound of formula (XI) can be cyclized to a compound of formula (I-H) using step (2) of Scheme IX. The reaction can be carried out without solvent, at elevated temperatures, such as the temperature required to melt the compound of formula (XI). The reaction can also be carried out at room temperature or at elevated temperature in a suitable solvent. Suitable solvents include alcohols such as methanol, ethanol, trifluoroethanol, isopropanol, and tert-butanol; water; Acetonitrile; NMP; And toluene. Preferred solvents include trifluoroethanol, isopropanol, tert-butanol, and acetonitrile. Preferably, cyclization reaction temperature is 250 degrees C or less. Cyclization can be carried out at a temperature below 200 ° C. or at a temperature below 180 ° C. Optionally, bases can be used in the reaction. Suitable bases include triethylamine. Optionally, a catalyst such as pyridine hydrochloride, pyridinium p-toluenesulfonate, or p-toluenesulfonic acid can be added.

Compounds of formula (IH) can be converted to compounds of formula (X) wherein R ₂ is hydrogen using a variety of methods depending on the identity of E. Examples of these methods are shown in Schemes II to V, wherein R ₂ is hydrogen. Methods of synthesizing Schemes VI and VII can also be carried out using starting materials X _b and XXII, wherein R _2b and R ₂ are each hydrogen.

The objects and advantages of the present invention will be further illustrated by the following examples, but the specific materials and amounts thereof referred to in these examples, as well as other conditions and details, are not intended to unduly limit the present invention.

Example 1

Preparation of 1- [4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol

Part A

Triethylamine (13.1 mL, 94.1 mmol) was added to 3-amino-4-chloroquinoline in dichloromethane (125 mL) (Surrey et al., Journal of the American Chemical Society, 73, pp. 2413-2416 (1951) )] Was added to the solution of (11.2 g, 62.7 mmol) with stirring. Then a solution of ethoxyacetyl chloride (9.2 g, 75 mmol) in dichloromethane (35 mL) was added dropwise and the reaction was stirred at rt overnight. Analysis by liquid chromatography / mass spectrometry (LC / MS) indicated the presence of starting material and further dropwise addition of a solution of ethoxyacetyl chloride (2.3 g, 19 mmol) in dichloromethane (10 mL). The reaction was stirred at rt overnight. Saturated aqueous sodium bicarbonate (100 mL) was added and the resulting mixture was stirred at rt for 30 min. The organic layer was separated and washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and water (2 x 50 mL), dried over potassium carbonate, filtered and concentrated under reduced pressure to give N- (4-chloroquinoline-3 17.0 g of -yl) -2-ethoxyacetamide was obtained as a dark oil, which was left to crystallize.

Part B

N- (4-chloroquinolin-3-yl) -2-ethoxyacetamide (4.5 g, 17 mmol), 1-amino-2-methylpropan-2-ol (2.3 g, 26 mmol), and p- A mixture of toluenesulfonic acid monohydrate (150 mg, 0.79 mmol) was placed in a TEFLON-lining pressure vessel, heated at 125 ° C. for 15 hours and allowed to cool to room temperature. Dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (25 mL) were added and the mixture was stirred for 15 minutes. The organic layer was separated and washed sequentially with saturated aqueous sodium bicarbonate (2 × 35 mL) and water (25 mL), dried over potassium carbonate, filtered and concentrated under reduced pressure to give 1- [2- (ethoxymethyl 4.6 g))-1H-imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol was obtained as a dark brown oil.

HRMS (ESI) calcd for C ₁₇ H ₂₁ N ₃ 0 ₂ (M + H ⁺ ): 300.1712, found 300.1713.

Part C

1- [2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol (0.98 g, 3.3 mmol in dichloromethane (35 mL) ) Solution was cooled to approximately 0 ° C. and 3-chloroperoxybenzoic acid (approximately 77% pure material 1.1 g, 5 mmol) was added. The reaction was stirred at 0 ° C. for 10 minutes, at room temperature for 3 hours, diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (35 mL) and stirred for 15 minutes. The aqueous layer was separated, extracted with dichloromethane (3 × 25 mL), and the combined organic fractions were dried over potassium carbonate, filtered and concentrated under reduced pressure to give 1- [2- (ethoxymethyl) -5-oxido. 0.96 g of -1H-imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol was obtained as a brown oil.

HRMS (ESI) calc'd for C ₁₇ H ₂₁ N ₃ O ₃ (M + H ⁺ ): 316.1661, found 316.1664.

Part D

1- [2- (ethoxymethyl) -5-oxido-1H-imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol in dichloromethane (35 mL) 0.96 g, 3.0 mmol) was cooled to 0 ° C. and trichloroacetyl isocyanate (0.60 mL, 5.0 mmol) was added with stirring. The reaction was stirred at 0 ° C. for 15 minutes and then at room temperature overnight. Methanol (10 mL) was added and the mixture was stirred for 15 minutes and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and sodium methoxide (25% w / w solution in methanol, 0.25 mL) was added. The mixture was stirred at rt for 3 h. Analysis by LC / MS indicated the reaction was not complete and additional sodium methoxide solution (1.0 mL) was added. The reaction was stirred overnight at room temperature and determined to be incomplete. Hydrochloric acid (10% w / w, 5 mL) was added and the mixture was stirred for 1 hour. Saturated aqueous sodium bicarbonate (15 mL) and aqueous sodium hydroxide (50% w / w, 10 drops) were added and the reaction stirred overnight at room temperature. Analysis by LC / MS again showed that the reaction was not complete. Potassium hydroxide (0.5 N solution in methanol, 5 mL) was added and the reaction mixture was heated at reflux for 4 hours, allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (75 mL) and the solution washed with water (2 × 50 mL), dried over potassium carbonate, filtered and concentrated under reduced pressure. The residue (0.64 g) was purified by column chromatography on silica gel eluting with 5% methanol in dichloromethane containing 2 mL aqueous ammonium hydroxide per liter of eluent. The resulting solid was recrystallized from methanol / water, recrystallized three times from methanol and dried at 70 ° C. under vacuum overnight to give 1- [4-amino-2- (ethoxymethyl) -1H-imidazo [4, 5-c] quinolin-1-yl] -2-methylpropan-2-ol was obtained as a tan needle (mp 192-194 ° C.).

MS (APCI) m / z 315 (M + H ⁺ ); HRMS (ESI) calc'd for C ₁₇ H ₂₂ N ₄ O ₂ (M + H ⁺ ): 315.1821, found 315.1819.

Analytical Calcd for C ₁₇ H ₂₂ N ₄ O ₂ : C, 64.95; H, 7.05; N, 17.82. Found: C, 64.94; H, 6.94; N, 17.74.

Example 2

N- [4- (4-amino-2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide

Manufacture

Part A

A solution of 3-amino-4-chloroquinoline (5.0 g, 28 mmol) and triethylamine (5.8 mL, 42 mmol) in dichloromethane (100 mL) was cooled to approximately 0 ° C. Then a solution of propionyl chloride (2.8 g, 31 mmol) in dichloromethane (15 mL) was added dropwise over 15 minutes, the reaction was allowed to warm to room temperature and stirred overnight. Analysis by high performance liquid chromatography (HPLC) indicated the presence of starting material, further adding triethylamine (1.95 mL, 14.0 mmol) and propionyl chloride (0.85 g, 9.2 mmol) in dichloromethane (5 mL). Added. The reaction was stirred overnight at room temperature; Dilute with dichloromethane (100 mL); Washed sequentially with water, saturated aqueous sodium carbonate, 10% w / w aqueous sodium hydroxide, saturated aqueous sodium carbonate, and brine; Dry over magnesium sulfate and sodium sulfate, filter and concentrate under reduced pressure. The resulting brown solid (8.1 g) was recrystallized from toluene to give 4.5 g of N- (4-chloroquinolin-3-yl) propanamide as a beige plate material (mp 151-152 ° C.).

Part B

In a glass-lining pressure vessel, N- (4-chloroquinolin-3-yl) propanamide (3.3 g, 14 mmol), N- (4-aminobutyl) methanesulfonamide hydro in trifluoroethanol (35 mL) A solution of chloride (see Example 199 of US Patent Application Publication No. 2004/0147543, 3.14 g, 15.5 mmol), and triethylamine (3.9 mL, 28 mmol) was heated at 150 ° C. for 16 hours and allowed to cool to room temperature. Put it. The volatiles were removed under reduced pressure and the resulting amber paste was dissolved in dichloromethane. The solution was washed sequentially with diluted aqueous ammonium chloride, saturated aqueous sodium carbonate (2 ×), and brine; Dried over magnesium sulfate and sodium sulfate; Filtered; Concentrated under reduced pressure. The resulting amber syrup (4.8 g) was recrystallized from hot propyl acetate. The crystals were washed with profile acetate to give 3.8 g of N- [4- (2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide as light amber granules (mp 166-). 168 ° C.).

Part C

Solid 3-chloroperoxybenzoic acid (approximately 2.7 g of 77% pure material, 13 mmol) was added N- [4- (2-ethyl-1H-imidazo [4,5-c] quinoline- in dichloromethane (75 mL). To the solution of 1-yl) butyl] methanesulfonamide (3.8 g, 11 mmol) was added portionwise. The reaction was stirred for 5 hours at room temperature. Analysis by HPLC indicated the presence of starting material and additional 3-chloroperoxybenzoic acid (0.5 g) was added. The reaction was stirred for 1 hour at room temperature and ammonium hydroxide (50 mL) was added. The resulting mixture was stirred vigorously for 15 minutes at room temperature, then p-toluenesulfonyl chloride (2.5 g, 0.013 mol) was added in one portion. The mixture was stirred vigorously overnight at room temperature. A fine solid was provided which was collected by vacuum filtration (3.4 g) and recrystallized from ethanol (100 mL). The crystals were dried in a vacuum oven at 60 ° C. for 4 hours to yield N- [4- (4-amino-2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide 3.0 g was obtained as pale yellow feathery crystals (mp 198-200 ° C.).

MS (APCI) m / z 362 (M + H) ⁺ ;

Analytical Calcd for C ₁₇ H ₂₃ N ₅ O ₂ S: C, 56.49; H, 6. 41; N, 19.37. Found: C, 56.31; H, 6. 49; N, 19.13.

Example 3

N- {2- [4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -1,1-dimethylethyl} methanesulfonamide monohydrate Produce

Part A

A solution of 1,2-diamino-2-methylpropane (11.9 mL, 113 mmol), tert-butyl phenyl carbonate (42.1 mL, 227 mmol) and pure ethanol (500 mL) was 20.5 at a reflux temperature under a nitrogen atmosphere. Heated for hours. The volatiles were removed under reduced pressure and the residue was dissolved in water (560 mL). Hydrochloric acid (IN, 140 mL) was added to the solution to adjust to approximately pH 3 and washed with dichloromethane (2 x 1 L). Then aqueous sodium hydroxide (2N, 70 mL) was added to the aqueous solution to adjust to approximately pH 12 and extracted with dichloromethane (5 x 800 mL). The combined extracts were dried over sodium sulphate, filtered, concentrated under reduced pressure and further dried under vacuum to afford 13.05 g of tert-butyl 2-amino-2-methylpropylcarbamate, which was combined with material obtained from other runs. It was.

Part B

A solution of tert-butyl 2-amino-2-methylpropylcarbamate (20.8 g, 111 mmol) and triethylamine (23.2 mL, 167 mmol) in dichloromethane (125 mL) was cooled to -9 ° C. A solution of methanesulfonic anhydride (21.25 g, 122 mmol) in dichloromethane (106 mL) was added over 50 minutes keeping the reaction temperature below -4 ° C. After addition, the reaction is stirred for 30 minutes; Dilute with dichloromethane (80 mL); Washed sequentially with brine (30 mL), saturated aqueous ammonium chloride (30 mL), 10% w / w hydrochloric acid (20 mL), brine (10 mL), saturated aqueous sodium carbonate (20 mL), and brine (10 mL) and; Dry over magnesium sulfate, filter, concentrate under reduced pressure and dry under vacuum to afford tert-butyl 2-methyl-2-[(methylsulfonyl) amino] propylcarbamate.

Part C

Hydrogen chloride (153 mL of 4 N solution in 1,4-dioxane) was cooled to 0 ° C. and stirred. The material from Part B was added in portions, then washed with ethanol. The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the residue was concentrated twice from ethanol and dried under vacuum to afford N- (2-amino-1, 1-dimethylethyl) methanesulfonamide hydrochloride.

Part D

In a glass-lining pressure vessel, N- (4-chloroquinolin-3-yl) -2-ethoxyacetamide (2.0 g, 7.6 mmol) in trifluoroethanol (30 mL), N- (2-amino- A solution of 1,1-dimethylethyl) methanesulfonamide hydrochloride (2.16 g, 10.7 mmol), and triethylamine (2.6 mL, 19 mmol) was heated at 150 ° C. for 16 h. Analysis by HPLC indicated the presence of starting material and additionally N- (2-amino-1,1-dimethylethyl) methanesulfonamide hydrochloride (0.5 g) and triethylamine (0.3 mL). The heating was continued for an additional 16 hours. The volatiles were removed under reduced pressure and the resulting amber paste was dissolved in dichloromethane. The solution was washed sequentially with diluted aqueous ammonium chloride, saturated aqueous sodium carbonate (2 ×), and brine; Dried over magnesium sulfate and sodium sulfate; Filtered; Concentrated under reduced pressure. The resulting amber syrup (4 g) was purified by column chromatography on silica gel to give N- {2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -1,1 1.6 g of -dimethylethyl} methanesulfonamide were obtained as amber syrup.

Part E

Solid 3-chloroperoxybenzoic acid (approximately 77% pure material 1.1 g, 5 mmol) was added N- {2- (ethoxymethyl) -1H-imidazo [4,5-c] quinoline in dichloromethane (30 mL). -1-yl] -1,1-dimethylethyl} methanesulfonamide (1.6 g, 4.2 mmol) was added in portions. The reaction was stirred for 3 hours at room temperature. Analysis by HPLC indicated the presence of small amounts of starting material and additional 3-chloroperoxybenzoic acid (0.2 g) was added. The reaction was stirred for 1 hour at room temperature and ammonium hydroxide (30 mL) was added. The resulting mixture was stirred vigorously for 15 minutes at room temperature, then p-toluenesulfonyl chloride (0.97 g, 0.0051 mol) was added in one portion. The reaction mixture is stirred vigorously for 2 hours at room temperature, diluted with dichloromethane, washed sequentially with saturated aqueous sodium carbonate (2 x) and brine (1 x), dried over sodium sulfate and magnesium sulfate, filtered, and reduced pressure Concentration under gave amber syrup. The syrup was purified by column chromatography on silica gel (eluted with dichloromethane) and then recrystallized from propyl acetate (10 mL / g) to give 0.8 g of a tan solid. The solid was recrystallized from ethanol (4 mL) and water (two drops) and the crystals were dried for 4 hours at 60 ° C. in a vacuum oven to give N- {2- [4-amino-2- (ethoxymethyl) -1H 0.55 g of imidazo [4,5-c] quinolin-1-yl] -1,1-dimethylethyl} methanesulfonamide monohydrate was obtained as pale yellow crystals (mp 161-163 ° C.).

MS (ESI) m / z 392 (M + H) ⁺ ;

Analytical Calcd for C ₁₈ H ₂₅ N ₅ 0 ₃ S.1.0 H ₂ O: C, 52.79; H, 6.65; N, 17.10. Found: C, 52.69; H, 6.56; N, 16.87.

Example 4

Preparation of N- [4- (2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide

A mixture of N- (4-chloroquinolin-3-yl) propanamide (0.1 g, 0.4 mmol) and N- (4-aminobutyl) methanesulfonamide hydrochloride (0.095 g, 0.5 mmol) was sealed in a vial and Heated at 125 ° C. for 16 h and allowed to cool to rt. Water was added and sodium carbonate was added to the solution to adjust to approximately pH 10. The aqueous solution was extracted twice with dichloromethane (50 mL) and the combined extracts were washed with brine, dried over magnesium sulfate and sodium sulfate, filtered and concentrated under reduced pressure. Analysis by HPLC and mass spectrometry proved that N- [4- (2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide is the main product. MS (APCI) m / z 347 (M + H) ⁺ .

Examples 5 and 6

Preparation of N- [4- (2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide

N- (4-chloroquinolin-3-yl) propanamide (0.05 g, 0.2 mmol), N- (4-aminobutyl) methanesulfonamide hydrochloride (0.047 g, 0.2 mmol), and triethyl in the solvents shown below A solution of amine (0.059 mL, 0.40 mmol) was sealed in a vial and heated at 128 ° C. for 48 hours. Analysis by HPLC showed N- [4- (2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide to N- (4-chloroquinoline-3- The ratio of 1) propanamide is shown.

Example menstruum Product: Departure Material 5 tert-butanol 93: 7 6 Isopropanol 92: 8

Example 7

Preparation of 2-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] [1,5] naphthyridin-4-amine

Part A

The Parr vessel was flushed with nitrogen and charged with platinum on carbon 5% (1.1 g) and water (5 mL). A solution of triethylamine (23.3 g, 0.230 mol) and 3-nitro [1,5] naphthyridin-4-ol (22.0 g, 0.115 mol) in water (1.1 L) was added and the mixture was subjected to hydrogen pressure (35 psi, 2.4 x 10 ⁵ Pa) for 3 hours, and then filtered through a layer of CELITE filter. The filtrate was concentrated to a volume of 400 mL by flash evaporation at 75 ° C. and left to cool. A solid formed which was collected by vacuum filtration to give 3-amino [1,5] naphthyridin-4-ol (16.4 g) as a light mustard powder (mp 315-320 ° C.).

MS (ESI) m / z 162 (M + H) ⁺ .

Part B

Phosphorous oxychloride (4) (47.0 g, 0.304 mol) was converted to 3-amino [1,5] naphthyridin-4-ol (20.0 g, 0.124 mol) in N, N-dimethylformamide (DMF) (200 mL). To the mixture over 30 minutes; The reaction temperature was maintained at 10 ° C.-20 ° C. during the dropwise addition. When the dropwise addition was complete, the reaction was stirred at room temperature for 3 hours, heated to 90 ° C. for 15 minutes and allowed to cool to room temperature. Water (150 mL) and ice were added keeping the temperature below 55 ° C. The mixture was stirred at rt for 30 min, heated at 100 ° C. for 3 h and allowed to cool to rt overnight. The resulting black solution was basified by the slow addition of solid sodium carbonate and saturated aqueous sodium carbonate. The basic solution was extracted three times with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate and magnesium sulfate and concentrated under reduced pressure to give a viscous amber paste. The paste was triturated with warm diethyl ether for 30 minutes and the resulting solid was collected by vacuum filtration to give 4-chloro [1,5] naphthyridin-3-amine (11 g) as brown granules (mp 188-190 ° C.). Obtained).

MS (ESI) m / z 180 (M + H) ⁺ .

Part C

Cool a solution of 4-chloro [1,5] naphthyridin-3-amine (4.0 g, 0.022 mol) and triethylamine (4.6 mL, 0.033 mol) in 1,2-dichloroethane (80 mL) to 3 ° C. I was. A solution of acetyl chloride (4.4 g, 0.056 mol) in 1,2-dichloroethane (5 mL) was added dropwise over 5 minutes. The reaction is then heated at reflux for 5 hours; Allowed to cool to room temperature; Dilute with dichloromethane (100 mL); Washed sequentially with saturated aqueous sodium carbonate (2 ×), water (1 ×), and brine (1 ×); Dried over sodium sulfate and magnesium sulfate; Filtered; Concentration under reduced pressure gave 4.7 g of a dark brown solid. The solid was recrystallized from acetonitrile (20 mL) and collected in two aliquots to give N- (4-chloro [1,5] naphthyridin-3-yl) acetamide (3.0 g) as a brown solid.

MS (ESI) m / z 222 (M + H) ⁺ .

Part D

A mixture of N- (4-chloro [1,5] naphthyridin-3-yl) acetamide (1.6 g, 0.073 mol) and isobutylamine (7.3 mL, 0.0722 mol) was heated to 120 ° C. overnight in a sealed vial And allowed to cool to room temperature and added to a solution of water (100 mL) and saturated aqueous sodium carbonate (20 mL). A precipitate formed. The mixture was stirred at rt for 1.5 h, the precipitate was collected by vacuum filtration and dried on a filtration funnel to afford 2-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] [1 , 5] naphthyridine (1.45 g) was obtained as a gray powder (mp 110-111 ° C.).

MS (APCI) m / z 241 (M + H) ⁺ .

Part E

Solid 3-chloroperoxybenzoic acid (1.8 g, approximately 77% pure material, 0.0078 mol) was added 2-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c in dichloromethane (30 mL). ] Added in portions to a solution of [1,5] naphthyridine (1.45 g, 0.0060 mol). The reaction was stirred at rt for 3 h and washed with saturated aqueous sodium carbonate (100 mL). The aqueous fraction was extracted three times with dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate and magnesium sulfate, filtered and concentrated under reduced pressure to afford 2-methyl-1- (2-methylpropyl) -5-oxido-1H-imidazo [4,5 -c] [1,5] naphthyridine (1.3 g) was obtained as a yellow solid.

MS (APCI) m / z 257 (M + H) ⁺ .

Part F

2-methyl-1- (2-methylpropyl) -5-oxido-1H-imidazo [4,5-c] [1,2 with vigorous stirring of p-toluenesulfonyl chloride (1.2 g, 0.0061 mol) 5] to a mixture of naphthyridine (1.3 g, 0.0051 mol), dichloromethane (25 mL), and ammonium hydroxide (17 mL). The reaction was stirred vigorously for 2 hours at room temperature, then stirring was stopped and the layers were allowed to separate for 2 hours. A precipitate formed which was collected by vacuum filtration to give 0.9 g of ivory needle-like material. The needle-like material was recrystallized from isopropanol (12 mL) and the collected crystals were dried in a vacuum oven at 60 ° C. for 5 hours to give 2-methyl-1- (2-methylpropyl) -1H-imidazo [4,5- c] [1,5] naphthyridin-4-amine (0.7 g) was obtained as a colorless needles (mp 227-229 ° C.).

MS (ESI) m / z 256 (M + H) ⁺ ;

Analytical Calcd for C ₁₄ H ₁₇ N ₅ : C, 65.86; H, 6. 71; N, 27.43. Found: C, 65.53; H, 6.68; N, 27.35.

Example 8

Preparation of 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline

Part A

Formic acid (0.36 mL) was added slowly to acetic anhydride (0.8 mL) with stirring, and the reaction was stirred at room temperature for 2.75 hours, then 3-amino-4-chloroquinoline (0.50 g, in tetrahydrofuran (5 mL), 2.8 mmol) in solution. The resulting mixture was stirred for 1 hour at room temperature. A solid was present which was collected by filtration and washed with diethyl ether to give 0.48 g of 4-chloroquinolin-3-ylformamide as a beige solid (mp 175-177 ° C.).

Part B

A mixture of 4-chloroquinolin-3-ylformamide (0.050 g, 0.24 mol) and isobutylamine (0.25 mL, 2.4 mmol) was heated to 110 ° C. overnight in a sealed vial and allowed to cool to room temperature. Dichloromethane (1 mL) and aqueous ammonium chloride (10% w / w, 1 mL) were added. The organic layer was separated, washed with 10% w / w aqueous ammonium chloride, dried over sodium sulfate, concentrated under reduced pressure and dried at 35 ° C. in a vacuum oven overnight to yield 41 mg of a brown crystalline solid, which was LC / MS Analysis by showed that it was a mixture of 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline and 3-amino-4-chloroquinoline.

Example 9

Preparation of 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline

Part A

Phosphorous oxychloride (90 mL, 0.97 mol) was added dropwise to a stirred slurry of 3-aminoquinolin-4-ol hydrochloride (150 g, 0.76 mol) in 500 mL DMF. During the dropping the temperature of the mixture rose to about 100 ° C. After allowing the reaction mixture to cool to room temperature, about 2/3 of the DMF was removed under reduced pressure. The mixture was then filtered and the solid was dried to give N '-(4-chloroquinolin-3-yl) -N, N-dimethylimidoformamide (118 g), MS (ESI) m / z 234 ( M + H) ⁺ .

Part B

The glass vial was filled with N '-(4-chloroquinolin-3-yl) -N, N-dimethylimidoformamide (0.10 g, 0.40 mmol), isobutylamine (0.50 mL, 5.4 mmol), and pyridinium p-toluene Filled with sulfonate (5 mg, 0.02 mmol). The vial was placed in a steel pressure reactor and the vessel was heated to 150 ° C. in an oven for 15 hours. After cooling to room temperature, the reaction mixture was examined by liquid chromatography / mass spectrometry and the reaction was complete and the vessel was placed back in the oven and heated at 175 ° C. for 15 hours. After cooling to room temperature, the reaction mixture was examined by liquid chromatography / mass spectrometry and the main product of the reaction was 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline, MS (ESI ) m / z 226 (M + H) ⁺ .

Example 10

Preparation of 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline

The flask was charged with 3-aminoquinolin-4-ol hydrochloride (1.0 g, 5.1 mmol), 20 mL of acetonitrile and 1.5 mL of DMF. Phosphorous oxychloride (0.7 mL, 7.5 mmol) was added to the stirred slurry. The mixture was stirred at ambient temperature for 21 hours. The mixture was filtered to remove solids and washed with acetonitrile. Isobutylamine (2.5 mL, 25.5 mmol) was added to the filtrate. Exotherm was observed upon addition and the solution became a slurry. The mixture was placed in a glass pressure vessel and heated to 120 ° C. in an oven for 3 hours. After cooling to room temperature, the reaction mixture was examined by liquid chromatography / mass spectrometry and the reaction was almost complete. The slurry was dissolved in 50 mL of water and 50 mL of dichloromethane. The layers were separated. The aqueous layer was extracted with 25 mL of dichloromethane and combined with the separated dichloromethane layer. Examination of the combined dichloromethane layers by liquid chromatography / mass spectrometry revealed that the main product was 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline, MS (ESI) m / z 226 (M + H) ⁺ . The layer was dried over magnesium sulfate, filtered and concentrated to give 0.17 g (15%) of a viscous amber residue.

The complete disclosure of the patents, patent documents, and publications mentioned herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and variations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. The present invention is not to be unduly limited by the illustrative embodiments and examples described herein, such examples and embodiments are provided by way of example only, and the scope of the invention is limited only by the claims set forth herein below. It should be understood that

Claims (93)

Providing a compound of formula IV, and Reacting a compound of formula IV with an amine of formula R ₁ NH ₂ to provide 1H-imidazo [4,5-c] pyridine or an analog thereof, or a pharmaceutically acceptable salt thereof A method of preparing a 1H-imidazo [4,5-c] pyridine compound or an analog thereof, or a pharmaceutically acceptable salt thereof. <Formula IV>

<Formula I>

In the formula, E is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -OS (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is alkyl Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by halo, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl Or; or E combines with adjacent pyridine nitrogen atoms of Formulas I and IV to form a ring with fused tetrazole in Formulas I-1 and IV-1; <Formula I-1>

<Formula IV-1>

L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -OS (O) ₂ -R ', wherein R' is alkyl, halo, or alkyl optionally substituted by nitro, Haloalkyl, and aryl; R _A and R _B are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups; R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R 1') -X 1 -Y 1 -R 4 And -N (R ₁ ′) -X ₁ -R _5b ; R ₂ is selected from the group consisting of _{-R 4, -XR 4, -XYR 4} , and -XR _5; R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ ; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene or heterocyclylene May be optionally interrupted or terminated by and optionally interrupted by one or more -O- groups; X ₁ is C _{2 -20} alkylene; Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O ) -O-, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ )- Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And

It is selected from the group consisting of; Y ₁ is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q-, -C (R ₆ ) -N ( R ₈ )-, -OC (R ₆ ) -N (R ₈ )-, and

It is selected from the group consisting of; Z is a bond or -O-; R ₁ 'is selected from hydrogen, C _{1 -20} alkyl, hydroxy -C _{2 -20} alkylenyl, and alkoxy -C _{2 -20} group consisting of alkylenyl; R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero The aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy , Heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and (alkyl, alkenyl, alkynyl, and heterocycles In case of reel ) May be substituted by one or more substituents independently selected from the group consisting of oxo; R ₅ is

And

It is selected from the group consisting of; R _5b is

It is selected from the group consisting of; R ₆ is selected from the group consisting of = O and = S; R ₇ is C _{2 -7} alkylene; R ₈ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl; R ₉ is selected from the group consisting of hydrogen and alkyl; R ₁₀ is C _{3 -8} alkylene; A is selected from the group consisting of -O-, -C (O)-, -S (O) _0-2- , and -N (R ₄ )-; A 'is -O-, -S (O) _0-2 - it is selected from the group consisting _{of, -N (-QR 4) - -} , and -CH _2; Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group; V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ; V 'is selected from the group consisting of -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ; W is selected from the group consisting of a bond, -C (O)-, and -S (O) _2- ; a and b are the integers of 1-6 independently, provided a + b is 7 or less. The process of claim 1, wherein the step of providing a compound of formula III, and the compound of formula III are selected from the group consisting of carboxylic acid halides of formula hal-C (O) -R ₂ , wherein hal is chloro or bromo, or Reacting with anhydrides or mixed anhydrides of (—C (O) —R ₂ ) ₂ to provide a compound of formula IV. <Formula III>

The method of claim 2, further comprising providing a compound of Formula II and reducing the compound of Formula II to provide a compound of Formula III. <Formula II>

The method of claim 2, further comprising providing a compound of Formula VI and converting the hydroxy group at the 4-position of Formula VI to the L group to provide a compound of Formula III. <Formula VI>

The method of claim 1, further comprising providing a compound of Formula VII and converting the hydroxy group at the 4-position of Formula VII to the L group to provide a compound of Formula IV. <Formula VII>

The method of claim 5, wherein the step of providing a compound of formula VI, and the compound of formula VI are selected from the group consisting of a carboxylic acid halide of formula hal-C (O) -R ₂ , wherein hal is chloro or bromo, or Reacting with anhydrides or mixed anhydrides of (—C (O) —R ₂ ) ₂ to provide a compound of formula (VII). <Formula VI>

The method of claim 4 or 6, further comprising providing a compound of formula V and reducing the compound of formula V to provide a compound of formula VI. <Formula V>

Providing a compound of Formula VIII, Reacting a compound of formula VIII with an amine of formula R ₁ NH ₂ to provide 1H-imidazo [4,5-c] pyridine or an analog thereof, or a pharmaceutically acceptable salt thereof A method of preparing a 1H-imidazo [4,5-c] pyridine compound or an analog thereof, or a pharmaceutically acceptable salt thereof. <Formula VIII>

<Formula I>

In the formula, E is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -OS (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is alkyl Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by halo, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl Or; or E combines with adjacent pyridine nitrogen atoms of Formulas I and VIII to form a ring with fused tetrazole in Formulas I-1 and IX; <Formula I-1>

<Formula IX>

L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -OS (O) ₂ -R ', wherein R' is alkyl, halo, or alkyl optionally substituted by nitro, Haloalkyl, and aryl; R _A and R _B are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups; R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R 1') -X 1 -Y 1 -R 4 And -N (R ₁ ′) -X ₁ -R _5b ; R ₂ is hydrogen; R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ ; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene or heterocyclylene May be optionally interrupted or terminated by and optionally interrupted by one or more -O- groups; X ₁ is C _{2 -20} alkylene; Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O ) -O-, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ )- Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And It is selected from the group consisting of; Y ₁ is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q-, -C (R ₆ ) -N ( R ₈ )-, -OC (R ₆ ) -N (R ₈ )-, and

It is selected from the group consisting of; Z is a bond or -O-; R ₁ 'is selected from hydrogen, C _{1 -20} alkyl, hydroxy -C _{2 -20} alkylenyl, and alkoxy -C _{2 -20} group consisting of alkylenyl; R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero The aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy , Heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and (alkyl, alkenyl, alkynyl, and heterocyclyl in case of) May be substituted by one or more substituents independently selected from the group consisting of oxo; R ₅ is

, And

It is selected from the group consisting of; R _5b is

It is selected from the group consisting of; R ₆ is selected from the group consisting of = O and = S; R ₇ is C _{2 -7} alkylene; R ₈ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl; R ₉ is selected from the group consisting of hydrogen and alkyl; R ₁₀ is C _{3 -8} alkylene; R ₁₁ and R ₁₂ are independently is C _{1 -4} alkyl, or R ₁₁ and R ₁₂ is -O-, -N (C _{1 -4} alkyl), together with the nitrogen atom to which they are attached - a, or -S-, optionally To form 5- or 6-membered rings containing; A is selected from the group consisting of -O-, -C (O)-, -S (O) _0-2- , and -N (R ₄ )-; A 'is -O-, -S (O) _0-2 - it is selected from the group consisting _{of, -N (-QR 4) - -} , and -CH _2; Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group; V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ; V 'is selected from the group consisting of -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ; W is selected from the group consisting of a bond, -C (O)-, and -S (O) _2- ; a and b are the integers of 1-6 independently, provided a + b is 7 or less. The method of claim 8, further comprising forming an intermediate of Formula XI after reacting the compound of Formula VIII with an amine of Formula R ₁ NH ₂ . <Formula XI>

10. The process of claim 9, wherein the intermediate of formula (XI) is isolated after reacting a compound of formula (VIII) with an amine of formula (R ₁ NH ₂₎ . The compound of claim 8 or 9, wherein the compound of formula VI is provided, the hydroxy group at the 4-position is converted to an L group, and the amino group at the 3-position is represented by the formula HC (O) —N (R ₁₁ ) R _12. Reacting with formamide of to provide a compound of formula VIII. The process of claim 11, wherein the compound of formula VIII is provided without isolation before reacting with an amine of formula R ₁ NH ₂ . Providing a compound of Formula XI, To form 1H-imidazo [4,5-c] pyridine or an analog thereof, or a pharmaceutically acceptable salt thereof A method of preparing a 1H-imidazo [4,5-c] pyridine compound, or an analog thereof or a pharmaceutically acceptable salt thereof, comprising: <Formula XI>

<Formula I>

In the formula, E is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -OS (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is alkyl Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by halo, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl Or; or E combines with adjacent pyridine nitrogen atoms of Formulas I and XI to form a ring with a fused tetrazole in Formulas I-1 and XIII; <Formula I-1>

<Formula XIII>

L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -OS (O) ₂ -R ', wherein R' is alkyl, halo, or alkyl optionally substituted by nitro, Haloalkyl, and aryl; R _A and R _B are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups; R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R 1') -X 1 -Y 1 -R 4 , And -N (R ₁ ′) -X ₁ -R _5b , R ₂ is hydrogen; R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ ; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene or heterocyclylene May be optionally interrupted or terminated by and optionally interrupted by one or more -O- groups; X ₁ is C _{2 -20} alkylene; Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O ) -O-, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ )- Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And

It is selected from the group consisting of; Y ₁ is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q-, -C (R ₆ ) -N ( R ₈ )-, -OC (R ₆ ) -N (R ₈ )-, and

It is selected from the group consisting of; Z is a bond or -O-; R ₁ 'is selected from hydrogen, C _{1 -20} alkyl, hydroxy -C _{2 -20} alkylenyl, and alkoxy -C _{2 -20} group consisting of alkylenyl; R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero The aryleneyl, and heterocyclyl group is unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy , Heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and (alkyl, alkenyl, alkynyl, and heterocyclyl in case of ) May be substituted by one or more substituents independently selected from the group consisting of oxo; R ₅ is

And

It is selected from the group consisting of; R _5b is

It is selected from the group consisting of; R ₆ is selected from the group consisting of = O and = S; R ₇ is C _{2 -7} alkylene; R ₈ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl; R ₉ is selected from the group consisting of hydrogen and alkyl; R ₁₀ is C _{3 -8} alkylene; A is selected from the group consisting of -O-, -C (O)-, -S (O) _0-2- , and -N (R ₄ )-; A 'is -O-, -S (O) _0-2 - it is selected from the group consisting _{of, -N (-QR 4) - -} , and -CH _2; Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group; V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ; V 'is selected from the group consisting of -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ; W is selected from the group consisting of a bond, -C (O)-, and -S (O) _2- ; a and b are the integers of 1-6 independently, provided a + b is 7 or less. The compound of claim 13, wherein the compound of formula VI is provided, the hydroxy group at the 4-position is converted to an L group, and the amino group at the 3-position is reacted with formamide of the formula HC (O) —NH (R ₁ ). Further comprising providing a compound of Formula XI. <Formula VI>

The method of claim 14, wherein the compound of formula (XI) is provided without isolation before forming the compound of formula (I). 16. The method of any one of claims 11, 12, 14 and 15, further comprising providing a compound of formula V and reducing the compound of formula V to provide a compound of formula VI. <Formula V>

17. The method of any one of claims 1 to 16, further comprising the step of converting E to an amino group in the compound of formula I to provide a compound of formula X, or a pharmaceutically acceptable salt thereof. <Formula X>

18. The method of claim 17, wherein E is hydrogen, the compound of formula I is a compound of formula I-2, and the conversion of hydrogen to an amino group in the compound of formula I-2 comprises oxidizing the compound of formula I-2 Providing a 5N-oxide of Formula XX and aminating the compound of Formula XX to provide a compound of Formula X, or a pharmaceutically acceptable salt thereof. <Formula I-2>

<Formula XX>

18. The method of claim 17, wherein E is Hal, the compound of formula I is a compound of formula I-3, and the conversion of the Hal group to an amino group in the compound of formula I-3 comprises amination of the compound of formula I-3 To provide a compound of Formula X, or a pharmaceutically acceptable salt thereof. <Formula I-3>

Wherein Hal is fluoro, chloro, bromo, or iodo. 18. The method of claim 17, wherein E is hydroxy, the compound of formula I is a compound of formula I-4 and the step of converting a hydroxy group to an amino group in the compound of formula I-4 comprises Converting the hydroxy group in to a halo to provide a compound of formula (I-3) or a salt, and aminating the compound of formula (I-3) to provide a compound of formula (X), or a pharmaceutically acceptable salt thereof Way. <Formula I-4>

<Formula I-3>

Wherein Hal is fluoro, chloro, bromo, or iodo. 18. The method of claim 17, wherein E is hydroxy, the compound of formula I is a compound of formula I-4, and the step of converting a hydroxy group to an amino group in the compound of formula I-4 comprises: hal-S (O) ₂ A compound of formula (I-5) by sulfonating a compound of formula (I-4) by reacting with -R ', wherein hal is chloro or bromo), or a compound of formula O (-S (O) ₂ -R') ₂ And replacing the -OS (O) ₂ -R 'group in formula I-5 with an amino group of formula -N (Bn) ₂ to provide a compound of formula I-6, and removing the Bn protecting group of formula I-6 Thereby providing a compound of Formula X, or a pharmaceutically acceptable salt thereof. <Formula I-4>

<Formula I-5>

<Formula I-6>

18. The method of claim 17, wherein E is phenoxy, the compound of formula I is a compound of formula I-7, and the step of converting the phenoxy group to an amino group in the compound of formula I-7 comprises Amination to provide a compound of formula (X), or a pharmaceutically acceptable salt thereof. <Formula I-7>

In the formula, Ph is phenyl. 18. The group of claim 17, wherein E is -OS (O) ₂ -R ', the compound of formula I is a compound of formula I-5, and a -OS (O) ₂ -R' group in the compound of formula I-5 The step of converting to an amino group replaces the -OS (O) ₂ -R 'group with an amino group of formula -N (Bn) ₂ to provide a compound of formula I-6, and removes the Bn protecting group from formula I-6 Providing a compound of X, or a pharmaceutically acceptable salt thereof. <Formula I-5>

<Formula I-6>

The method of claim 17, wherein E is -N (Bn) ₂ , the compound of formula I is a compound of formula I-6, and the step of converting a -N (Bn) ₂ group to an amino group in the compound of formula I-6 comprises , Removing the Bn protecting group to provide a compound of Formula X, or a pharmaceutically acceptable salt thereof. <Formula I-6>

18. The process of claim 17, wherein E combines with an adjacent pyridine nitrogen atom of Formula I to form a ring with a fused tetrazole of Formula I-1, and converting the ring with an fused tetrazole in an compound of Formula I-1 to an amino group, Reacting the compound of formula (I-1) with triphenylphosphine to provide a compound of formula (XXI), and hydrolyzing the compound of formula (XXI) to provide a compound of formula (X), or a pharmaceutically acceptable salt thereof. How to be. <Formula I-1>

<Formula XXI>

18. The process of claim 17, wherein E combines with an adjacent pyridine nitrogen atom of Formula I to form a ring with a fused tetrazole in Formula I-1 and converting the ring with an fused tetrazole in an compound of Formula I-1 to an amino group And reductively removing the ring from the compound of formula (I-1) with tetrazole to provide a compound of formula (X), or a pharmaceutically acceptable salt thereof. <Formula I-1>

27. The method of any one of claims 1-7 and 17-26, wherein R ₂ is -R ₄ . The method of claim 27, wherein R ₂ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl. 29. The method of any one of claims 1 to 28, wherein R ₁ is -R ₄ or -XR ₄ . 30. The compound of claim 29, wherein -R ₄ is from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,2-dimethyl-4-oxopentyl, and (1-hydroxycyclobutyl) methyl And -XR ₄ is 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. The method of claim 30, wherein -R ₄ is 2-methylpropyl. 29. The method of any one of claims 1-28, wherein R ₁ is -XYR ₄ . Method in or -N (R ₈₎ -Q- - 33. The method of claim 32, wherein, X is an alkylene C _{2 -4,} Y is -S (O) _2. The compound of claim 33, wherein -XYR ₄ is 2- (propylsulfonyl) ethyl, 2-methyl-2-[(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and 2- (acetylamino) -2-methylpropyl. The method of any one of claims 1-28, wherein R ₁ is —XR ₅ . 36. The method of claim 35, wherein -XR ₅ is 4-[(morpholin-4-ylcarbonyl) amino] butyl. The compound of any one of claims 1-36, wherein R _A and R _B are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ . How to be. The method of claim 37, wherein R _A and R _B are each methyl. The compound of claim 1, wherein R _A and R _B together form a fused benzene ring, wherein the benzene ring is unsubstituted, substituted by one R group, or substituted on one R ₃ group. Or substituted by one R group and one R ₃ group. The method of claim 39, wherein the fused benzene ring is substituted by one R group selected from the group consisting of hydroxy and bromo. The method of claim 39, wherein the fused benzene ring is substituted by one R ₃ group, wherein R ₃ is methoxy, phenoxy, or benzyloxy. 37. The compound of any one of claims 1 to 36, wherein R _A and R _B together form a fused pyridine ring, wherein the fused pyridine ring is unsubstituted or substituted by one R group, or one R ₃ Substituted by a group or substituted by one R group and one R ₃ group; Where the fused pyridine ring is

Wherein the bond in bold indicates the position at which the ring is fused. 43. The method of claim 39 or 42, wherein R is hydroxy or bromo and R ₃ is methoxy, phenoxy, or benzyloxy. The method of claim 42, wherein the fused pyridine ring is substituted by one R group selected from the group consisting of hydroxy and bromo. The method of claim 42, wherein the fused pyridine ring is substituted by one R ₃ group, wherein R ₃ is methoxy, phenoxy, or benzyloxy. 27. The compound of any of claims 1-7 and 17-26, wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is R _2a , here: R _A1 and R _B1 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or R _A1 and R _B1 together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted, substituted by one R _a group, substituted by one R _3a group, or one Substituted by _a R _a group and one R _3a group; or R _A1 and R _B1 together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R _a groups; R _a is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, trifluoromethyl, alkoxy, alkylthio, and —N (R ₉ ) ₂ ; R _1a is -R _4a , -XR _4a , -XY _a -R _4a , -XY _a -XY _a -R _4a , -XR _5a , -N (R ₁ ') -QR _4a , -N (R ₁ ') -X ₁ -Y ₁ -R _4a , and -N (R ₁ ′) -X ₁ -R _5b ; R _2a is selected from the group consisting of _{-R 4a, -XR 4a, -XY a} -R 4a, and -XR _5a; R _3a is selected from the group consisting of -ZR _4a , -ZXR _4a , -ZXY _a -R _4a , -ZXY _a -XY _a -R _4a , and -ZXR _5a ; Y _a is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-,

,

,

,

, And

It is selected from the group consisting of; R _4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero Aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyl Independently selected from the group consisting of lenoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, and (dialkylamino) alkyleneoxy Substituted by one or more substituents; R _5a is

It is selected from the group consisting of. The method of claim 46, wherein R _2a is —R _4a . 48. The method of claim 47, wherein R _2a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl. 27. The compound of any of claims 8-26, wherein R _A is R _A1 , R _B is R _B1 , R ₁ is R _1a , R ₂ is hydrogen, wherein: R _A1 and R _B1 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or R _A1 and R _B1 together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted, substituted by one R _a group, substituted by one R _3a group, or 1 Substituted by 1 R _a group and 1 R _3a group; or R _A1 and R _B1 together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R ₃ groups; R _a is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, trifluoromethyl, alkoxy, alkylthio, and —N (R ₉ ) ₂ ; R _1a is -R _4a , -XR _4a , -XY _a -R _4a , -XY _a -XY _a -R _4a , -XR _5a , -N (R ₁ ') -QR _4a , -N (R ₁ ') -X ₁ -Y ₁ -R _4a , and -N (R ₁ ′) -X ₁ -R _5b ; R _3a is selected from the group consisting of -ZR _4a , -ZXR _4a , -ZXY _a -R _4a , -ZXY _a -XY _a -R _4a , and -ZXR _5a ; Y _a is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-,

,

,

,

, And

It is selected from the group consisting of; R _4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero Aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyl Independently selected from the group consisting of lenoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, and (dialkylamino) alkyleneoxy Substituted by one or more substituents; R _5a is

It is selected from the group consisting of. The method of any one of claims 46-49, wherein R ₁ is —R _4a or —XR _4a . 51. The compound of claim 50 wherein -R _4a is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, and (1-hydroxycyclobutyl) methyl, and -XR _4a is 2,2- Dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. The method of claim 51, wherein -R _4a is 2-methylpropyl. The method of any one of claims 46-49, wherein R _1a is —XY _a —R _4a . Method in or -N (R ₈₎ -Q- - 54. The method of claim 53, wherein, X is a C _{2 -4} alkylene, Y is _a -S (O) _2. The compound of claim 54, wherein -XY _a -R _4a is 2- (propylsulfonyl) ethyl, 2-methyl-2-[(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and 2- ( Acetylamino) -2-methylpropyl. The method of any one of claims 46-49, wherein R _1a is —XR _5a . The method of claim 56, wherein -XR _5a is 4-[(morpholin-4-ylcarbonyl) amino] butyl. The compound of any one of claims 46-57, wherein R _A1 and R _B1 are each independently from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ . Which method is chosen. 59. The method of claim 58, wherein R _A1 and R _B1 are each methyl. The compound of any one of claims 46-57, wherein R _A1 and R _B1 together form a fused benzene ring, wherein the benzene ring is unsubstituted or substituted by one R _a group, or one R _3a Or substituted by one R _a group and one R _3a group. 61. The method of claim 60, wherein the fused benzene ring is substituted by one R _a group selected from the group consisting of hydroxy and bromo. 61. The method of claim 60, wherein the fused benzene ring is substituted by one R _3a group, wherein R _3a is methoxy, phenoxy, or benzyloxy. 61. The method of claim 39 or 60, wherein the fused benzene ring is unsubstituted. The compound of any one of claims 46-57, wherein R _A1 and R _B1 together form a fused pyridine ring, wherein the fused pyridine ring is unsubstituted or substituted by one R _a group, or one R Substituted by _3a group or substituted by 1 R _a group and 1 R _3a group; Where the fused pyridine ring is

Wherein the bond in bold indicates the position at which the ring is fused. The method of claim 60 or 64, wherein R _a is hydroxy or bromo and R _3a is methoxy, phenoxy, or benzyloxy. 65. The method of claim 64, wherein the fused pyridine ring is substituted by one R _a group selected from the group consisting of hydroxy and bromo. 65. The method of claim 64, wherein the fused pyridine ring is substituted by one R _3a group, wherein R _3a is methoxy, phenoxy, or benzyloxy. 65. The method of claim 42 or 64, wherein the fused pyridine ring is unsubstituted. 46. The process according to any one of claims 1 to 7, and 17 to 45, wherein the reaction of the compound of formula IV with the amine of formula R ₁ NH ₂ is carried out at elevated temperature without solvent. 67. The process of any of claims 46-48, and 50-68, wherein formula IV is of formula IV _a, wherein the reaction of the compound of formula IV _a with the amine of formula R _1a NH ₂ is carried out without solvent. How to carry out at elevated temperature. <Formula IV _a >

46. The process of any one of claims 1 to 7, and 17 to 45, wherein the reaction of the compound of formula IV with an amine of formula R ₁ NH ₂ is carried out at elevated temperature in a solvent. 67. The process of any of claims 46-48, and 50-68, wherein formula IV is of formula IV _a, wherein the reaction of a compound of formula IV _a with an amine of formula R _1a NH ₂ is carried out in a solvent. How to carry out at elevated temperature. <Formula IV _a >

73. The solvent of claim 71 or 72 wherein the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, tert-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone, and toluene How. 74. The method of claim 73, wherein the solvent is selected from the group consisting of trifluoroethanol, isopropanol, and tert-butanol. 75. The method of any one of claims 69-74, wherein the elevated temperature is at least 80 ° C. 76. The method of any one of claims 69-75, wherein the elevated temperature is at least 110 ° C. 77. The method of any one of claims 69-76, wherein the elevated temperature is no greater than 180 ° C. 78. The method of any one of claims 69-77, wherein the elevated temperature is no greater than 165 ° C. The process according to any one of claims 8 to 12, 16 to 26, and 29 to 45, wherein the reaction of the compound of formula VIII with an amine of formula R ₁ NH ₂ is carried out without solvent. Way. The process according to any one of claims 8 to 12, 16 to 26, and 29 to 45, wherein the reaction of the compound of formula VIII with an amine of formula R ₁ NH ₂ is carried out in a solvent. Way. 81. The method of claim 80, wherein the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, tert-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone, toluene, and tetrahydrofuran How. 84. The method of claim 81, wherein the solvent is selected from the group consisting of trifluoroethanol, isopropanol, tert-butanol, and acetonitrile. A compound of formula (XI): or a pharmaceutically acceptable salt thereof. <Formula XI>

In the formula, E is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, phenoxy, -OS (O) ₂ -R ', and -N (Bn) ₂ , wherein R' is alkyl Is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted by halo, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl Or; or E combines with an adjacent pyridine nitrogen atom of Formula XI to form a ring with a fused tetrazole in Formula XIII; <Formula XIII>

L is selected from the group consisting of fluoro, chloro, bromo, iodo, phenoxy, and -OS (O) ₂ -R ', wherein R' is alkyl, halo, or alkyl optionally substituted by nitro, Haloalkyl, and aryl; R _A and R _B are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; or R _A and R _B together form a fused benzene ring or fused pyridine ring, wherein the benzene ring or pyridine ring is unsubstituted or substituted by one R group, substituted by one R ₃ group, or one R Substituted by a group and one R ₃ group; or R _A and R _B together form a fused 5- to 7-membered saturated ring optionally containing one nitrogen atom, wherein the fused ring is unsubstituted or substituted by one or more R groups; R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R ₉ ) ₂ ; R ₁ is _{-R 4, -XR 4, -XYR 4} , -XYXYR 4, -XR 5, -N (R 1 ') -QR 4, -N (R 1') -X 1 -Y 1 -R 4 , And -N (R ₁ ′) -X ₁ -R _5b , R ₃ is selected from the group consisting of -ZR ₄ , -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , and -ZXR ₅ ; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene or heterocyclylene May be optionally interrupted or terminated by and optionally interrupted by one or more -O- groups; X ₁ is C _{2 -20} alkylene; Y is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ )-, -OC (R ₆ )-, -OC (O ) -O-, -N (R ₈ ) -Q-, -OC (R ₆ ) -N (R ₈ )-, -C (R ₆ ) -N (OR ₉ )-, -ON (R ₈ )- Q-, -ON = C (R ₄ )-, -C (= NOR ₈ )-, -CH (-N (-OR ₈ ) -QR ₄ )-,

,

,

,

, And

It is selected from the group consisting of; Y ₁ is -O-, -S (O) _0-2- , -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -Q-, -C (R ₆ ) -N ( R ₈ )-, -OC (R ₆ ) -N (R ₈ )-, and

It is selected from the group consisting of; Z is a bond or -O-; R ₁ 'is selected from hydrogen, C _{1 -20} alkyl, hydroxy -C _{2 -20} alkylenyl, and alkoxy -C _{2 -20} group consisting of alkylenyl; R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and Heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylhetero The aryleneyl, and heterocyclyl groups are unsubstituted or alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy , Heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and (alkyl, alkenyl, alkynyl, and heterocycles In case of reel ) May be substituted by one or more substituents independently selected from the group consisting of oxo; R ₅ is

And

It is selected from the group consisting of; R _5b is

It is selected from the group consisting of; R ₆ is selected from the group consisting of = O and = S; R ₇ is C _{2 -7} alkylene; R ₈ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl; R ₉ is selected from the group consisting of hydrogen and alkyl; R ₁₀ is C _{3 -8} alkylene; A is selected from the group consisting of -O-, -C (O)-, -S (O) _0-2- , and -N (R ₄ )-; A 'is -O-, -S (O) _0-2 - it is selected from the group consisting _{of, -N (-QR 4) - -} , and -CH _2; Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group; V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ; V 'is selected from the group consisting of -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ; W is selected from the group consisting of a bond, -C (O)-, and -S (O) _2- ; a and b are the integers of 1-6 independently, provided a + b is 7 or less. 84. The compound or salt according to claim 83, wherein R ₁ is -R ₄ or -XR ₄ . 85. The compound of claim 84, wherein -R ₄ is from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,2-dimethyl-4-oxopentyl, and (1-hydroxycyclobutyl) methyl Or a compound or salt wherein -XR ₄ is 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. 86. The compound or salt according to claim 85, wherein -R ₄ is 2-methylpropyl. 84. The compound or salt according to claim 83, wherein R ₁ is -XYR ₄ . The method of claim 87, wherein X is C _{2 -4} alkylene, Y is -S (O) ₂ - or -N (R ₈₎ -Q- compound or salt. 89. The compound of claim 88, wherein -XYR ₄ is 2- (propylsulfonyl) ethyl, 2-methyl-2-[(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and 2- (acetylamino) Compound or salt selected from the group consisting of -2-methylpropyl. 84. The compound or salt according to claim 83, wherein R ₁ is -XR ₅ . 91. The compound or salt according to claim 90, wherein -XR ₅ is 4-[(morpholin-4-ylcarbonyl) amino] butyl. 92. The compound or salt of any one of claims 83-91, wherein R _A and R _B together form a fused benzene ring, wherein the benzene ring is unsubstituted. 92. The compound of any of claims 83-91, wherein R _A and R _B together form a fused pyridine ring, wherein the fused pyridine ring is unsubstituted, wherein the fused pyridine ring is

Wherein the bond in bold denotes the position at which the ring is fused.